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Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

There is experimental and clinical data to indicate the contribution of immune-escape mechanisms in relapsed/refractory pediatric leukemia. Studies have shown the accumulation of mutations that translate to peptides containing tumor-specific epitopes (neoantigens). The effectiveness of neoantigen-based vaccines has been shown in several clinical trials in adults. Though the initial results are encouraging, this knowledge must be developed to account for the uniqueness of pediatric cancer biology. We have completed the initial proof-of-concept analysis on a high-risk pediatric leukemia specimen and identified usable neoantigen sequences. We describe this approach, including the bioinformatics method and experimental model to verify their function that can be further broadened for personalized neoantigen prediction and testing for the generation of anticancer vaccines against high-risk pediatric leukemias.

Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intravenous Bu in pediatric patients before HSCT to first study the influence of glutathione‐s‐transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model‐based, first‐dose recommendation for intravenous Bu that can be widely used in pediatric patients. The model was built using data from 302 patients from five transplantation centers who received a Bu‐based conditioning regimen. External model validation used data from 100 patients. The relationship between body weight and Bu clearance (CL) was best described by an age‐dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1 metabolic groups based on GSTA1 polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first‐dose CL in the external cohort, with 81% of predicted area under the curves within the therapeutic window. The final model showed minimal bias (mean prediction error, −0.5%; 95% confidence interval [CI], −3.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage, 18.7%; 95% CI, 17.0%–20.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence of GSTA1 polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients.

Various reduced-intensity conditioning regimens are in use for allogeneic hematopoietic cell transplant (HSCT) in patients with idiopathic severe aplastic anemia (SAA). We describe the use of fludarabine, Campath, and low-dose cyclophosphamide (FCClow) conditioning in 15 children undergoing related or unrelated donor transplants. Total body irradiation (TBI) of 2 Gy was added for unrelated donor HSCT. At a median follow-up of 2.3 years, the failure-free survival was 100%, with low rates of infection and toxicity. There was no occurrence of grade III to IV acute graft-versus-host disease (GVHD). All patients had full donor myeloid chimerism post-HSCT, even with mixed chimerism in the T cell lineage. The absence of chronic GVHD and long-term stable mixed donor T cell chimerism confirms immune tolerance following FCClow (± TBI) conditioned transplantation in children with SAA.

Sinusoidal obstruction syndrome (SOS) is a well-recognized and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). SOS arises from endothelial cell damage and hepatocellular injury mostly due to the transplantation conditioning regimens but also to other patient, disease, and treatment-related factors. Understanding risk factors associated with the development of SOS is critical for early initiation of treatment or prophylaxis. The knowledge about genetic contribution is limited; few studies investigated so far selected a set of genes. To get more comprehensive insight in the genetic component, we performed an exome-wide association study using genetic variants derived from whole-exome sequencing. The analyses were performed in a discovery cohort composed of 87 pediatric patients undergoing HSCT following a busulfan-containing conditioning regimen. Eight lead single-nucleotide polymorphisms (SNPs) were identified after correction for multiple testing and subsequently analyzed in a validation cohort (n = 182). Three SNPs were successfully replicated, including rs17146905 ( P = .001), rs16931326 ( P = .04), and rs2289971 ( P = .03), located respectively in the UGT2B10, BHLHE22, and KIAA1715 genes. UGT2B10 and KIAA1715 were retained in a multivariable model while controlling for nongenetic covariates and previously identified risk variants in the GSTA1 promoter. The modulation of associations by conditioning regimens was noted; KIAA1715 was dependent on the intensity of the conditioning regimen, whereas the effect of UGT2B10 was equally applicable to all of them. Combined effect of associated loci was also observed ( P = .00006) with a genotype-related SOS risk of 9.8. To our knowledge, this is the first study addressing the genetic component of SOS at an exome-wide level and identifying novel genetic variations conferring a higher risk of SOS, which might be useful for personalized prevention and treatment strategies. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

The most frequent complication of allogeneic hematopoietic stem cell transplantation is acute Graft versus Host Disease (aGVHD). Proliferation and differentiation of donor T cells initiate inflammatory response affecting the skin, liver, and gastrointestinal tract. Besides recipient–donor HLA disparities, disease type, and the conditioning regimen, variability in the non-HLA genotype have an impact on aGVHD onset, and genetic variability of key cytokines and chemokines was associated with increased risk of aGVHD. To get further insight into the recipient genetic component of aGVHD grades 2–4 in pediatric patients, we performed an exome-wide association study in a discovery cohort (n = 87). Nine loci sustained correction for multiple testing and were analyzed in a validation group (n = 168). Significant associations were replicated for ERC1 rs1046473, PLEK rs3816281, NOP9 rs2332320 and SPRED1 rs11634702 variants through the interaction with non-genetic factors. The ERC1 variant was significant among patients that received the transplant from HLA-matched related individuals (p = 0.03), bone marrow stem cells recipients (p = 0.007), and serotherapy-negative patients (p = 0.004). NOP9, PLEK, and SPRED1 effects were modulated by stem cell source, and serotherapy (p < 0.05). Furthermore, ERC1 and PLEK SNPs correlated with aGVHD 3-4 independently of non-genetic covariates (p = 0.02 and p = 0.003). This study provides additional insight into the genetic component of moderate to severe aGVHD.

Background: Epstein–Barr virus (EBV) and cytomegalovirus (CMV) infections can have serious consequences during the period of aplasia and lymphopenia following hematopoietic stem cell transplantation (HSCT). Large pediatric cohort studies examining the effect of antiviral prophylaxis against these viruses are scarce. The present study aimed to analyse the potential effect of antiviral prophylaxis (acyclovir and famciclovir) on active post-transplant EBV and CMV infection in a pediatric cohort of allogeneic HSCT recipients. Methods: We used data from the TREASuRE cohort, consisting of 156 patients who had a first allogeneic HSCT, enrolled in four pediatric centers in Canada between July 2013 and March 2017. Follow-up was performed from the time of transplant up to 100 days post-transplant. Adjusted hazard ratio (HR) with 95% confidence intervals (CI) for the association between antiviral prophylaxis with acyclovir and/or famciclovir and EBV and CMV DNAemia was estimated using multivariate Cox regression models. Results: The post-transplant cumulative incidence of EBV and CMV DNAemia at 100 days of follow-up were, respectively, 34.5% (95% CI: 27.6–42.6) and 19.9% (95% CI: 14.5–27.1). For acyclovir, the adjusted hazard ratio (HR) for CMV and EBV DNAemia was 0.55 (95% CI: 0.24–1.26) and 1.41 (95% CI: 0.63–3.14), respectively. For famciclovir, the adjusted HR were 0.82 (95% CI: 0.30–2.29) and 0.79 (95% CI: 0.36–1.72) for CMV and EBV DNAemia, respectively. Conclusion: The antivirals famciclovir and acyclovir did not reduce the risk of post-transplant CMV and EBV DNAemia among HSCT recipients in our pediatric population.

Background Epstein-Barr virus (EBV) can cause severe disease following hematopoietic stem cell transplant (HSCT), including post-transplant lymphoproliferative disorder (PTLD). The objective was to analyze risk factors associated with post-transplant EBV outcomes among pediatric allogeneic HSCT recipients. Methods We used data from 156 pediatric allogeneic HSCT recipients enrolled in the Canadian multicenter TREASuRE study. Cox and Prentice-Williams-Petersen models were used to analyze risk factors for post-transplant EBV events including occurrence and recurrence of EBV DNAemia, increase in EBV viral load (EBV-VL), and preemptive use of rituximab, an effective therapy against PTLD. Results Females were at higher risk for increasing EBV-VL (adjusted hazard ratio (HR) = 2.83 [95% confidence intervals (CI): 1.33-6.03]) and rituximab use (HR = 3.08 [1.14-8.30]), but had the same EBV DNAemia occurrence (HR = 1.21 [0.74-1.99]) and recurrence risks (HR=1.05 [0.70-1.58]) compared to males. EBV DNAemia was associated with recipient pre-transplant EBV seropositivity (HR = 2.47 [1.17-5.21]) and with graft from an EBV-positive donor (HR = 3.53 [1.95-6.38]). Anti-thymocyte globulin (ATG) was strongly associated with all EBV outcomes, including the use of rituximab (HR = 5.33 [1.47-19.40]). Mycophenolate mofetil (MMF) significantly decreased the risk of all EBV events including the rituximab use (HR = 0.13 [0.03-0.63]). Conclusion This study in pediatric allogeneic HSCT patients reveals a reduced risk of all EBV outcomes with the use of MMF. Risk factors for EBV events such as EBV-VL occurrence and recurrence include EBV positivity in the donor and recipient, and use of ATG, whereas risk factors for the most severe forms of EBV outcome (EBV-VL and the use of rituximab) include female sex and ATG use.

Factors affecting the success of peripheral blood stem cell collection (SCC) in children are not well characterized. We reviewed 218 stem cell collections among 199 pediatric donors, of which 35 were from healthy sibling donors and 164 were for autologous collections. Successful SCC, defined as a CD34+ cell count of ≥2 × 106 /kg of recipient weight per intended transplant, occurred in 188 of 199 donors (94%). Ideal SCC defined ≥5 × 106 CD34+ cells/kg of recipient per intended transplant, occurred in 147 (74%) patients. Failure of collection occurred in 11 (6%) patients and was significantly associated with an autologous collection for a brain tumor diagnosis (P = .003) and a pre-apheresis peripheral blood (PB) CD34+ count

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients

BACKGROUND Sickle cell disease (SCD) is associated with renal complications starting as early as infancy. Allogeneic hematopoietic stem cell transplant (HSCT) treatments using newer nonmyeloablative (NMA) conditioning regimens show promising results in treating SCD in the pediatric population, but renal outcome parameters after transplantation have not been described. AIM To describe baseline renal parameters as well as short- and long-term renal outcomes in pediatric patients with SCD who underwent NMA-HSCT. METHODS A retrospective chart review of pediatric patients who received NMA-HSCT in Alberta, Canada. Short-term renal outcomes evaluated were: (1) acute kidney injury (AKI), (2) fluid overload (FO), and (3) hypertension. Long-term outcomes evaluated were: (1) estimated glomerular filtration rate (eGFR) development and at last follow-up with hyperfiltration defined as eGFR ≥ 150 mL/min/1.73 m2 , (2) proteinuria, and (3) hypertension. RESULTS The mean follow-up time was 128.6 weeks (standard deviations, 69.3). No posttransplant AKI events or FO were observed. eGFR remained > 90 mL/min/1.73 m2 at last follow-up in all patients, whereas hyperfiltration was present in eight (44.4%) and four (22.2%) patients pre- and post-HSCT, respectively, which are significantly different (P

Background Epstein-Barr virus (EBV) is carried in the blood of most adults, and transfusion-related infections have been reported. EBV is particularly deleterious in immunosuppressed transplant patients. The aim was to determine if EBV transmission occurred through leukodepleted blood product transfusion in pediatric recipients of hematopoietic stem cell transplants (HSCT). Study design and methods This prospective Canadian multi-center cohort study includes 156 allogeneic HSCT pediatric recipients. The association between EBV and transfusion was analyzed using Cox regressions. EBV infection, defined by a PCR+ test in the blood of seronegative recipients of an EBV-negative graft, was monitored in order to correlate the recipient EBV strain with that of the blood donors. EBV genotypes were determined by PCR amplification followed by DNA sequencing at two loci (EBNA3b and LMP1). Results No statistically significant associations were found between transfusions and EBV. One case of post-transplant EBV infection was identified among the 21 EBV-seronegative recipients receiving an EBV-negative graft. A total of 22 blood donors were retraced to determine whether the recipient's EBV strain matched that of a donor. One donor strain showed 100% sequence homology at the EBNA3b locus, but differed by one or two point mutations and by a 132-bp deletion at the LMP1 locus. The blood donor in question was alone among the 22 donors to show amplifiable virus in plasma. Blood from this donor readily produced an immortalized lymphoblastoid cell line in culture. Conclusion While considered a rare event, EBV transmission through transfusion may occur in the context of severe immunosuppression.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1− and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.

IntroductionPain negatively affects the health-related quality of life (HRQL) of adolescents with cancer. The Pain Squad+ smartphone-based application (app), has been developed to provide adolescents with real-time pain self-management support. The app uses a validated pain assessment and personalised pain treatment advice with centralised decision support via a registered nurse to enable real-time pain treatment in all settings. The algorithm informing pain treatment advice is evidence-based and expert-vetted. This trial will longitudinally evaluate the impact of Pain Squad+, with or without the addition of nurse support, on adolescent health and cost outcomes.Methods and analysisThis will be a pragmatic, multicentre, waitlist controlled, 3-arm parallel-group superiority randomised trial with 1:1:1 allocation enrolling 74 adolescents with cancer per arm from nine cancer centres. Participants will be 12 to 18 years, English-speaking and with ≥3/10 pain. Exclusion criteria are significant comorbidities, end-of-life status or enrolment in a concurrent pain study. The primary aim is to determine the effect of Pain Squad+, with and without nurse support, on pain intensity in adolescents with cancer, when compared with a waitlist control group. The secondary aims are to determine the immediate and sustained effect over time of using Pain Squad+, with and without nurse support, as per prospective outcome measurements of pain interference, HRQL, pain self-efficacy and cost. Linear mixed models with baseline scores as a covariate will be used. Qualitative interviews with adolescents from all trial arms will be conducted and analysed.Ethics and disseminationThis trial is approved by the Hospital for Sick Children Research Ethics Board. Results will provide data to guide adolescents with cancer and healthcare teams in treating pain. Dissemination will occur through partnerships with stakeholder groups, scientific meetings, publications, mass media releases and consumer detailing.Trial registration numberNCT03632343(ClinicalTrials.gov).

PURPOSE Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT. PATIENTS AND METHODS Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups’ historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored. RESULTS Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort ( P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients. CONCLUSION The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.

Carnitine is an essential cofactor for mitochondrial import and oxidation of fatty acids. High-dose chemotherapy and radiation, often required for hematopoietic stem cell transplant (HSCT), leads to tissue damage, mitochondrial dysfunction, and alterations in carnitine metabolism. The aim of this pilot cohort study was to describe plasma and urinary carnitine profiles during pediatric HSCT and their relationships with clinical outcomes. Plasma and urinary carnitine samples were collected from 22 pediatric patients before and through day 180 post-HSCT. Associations were observed between graft-versus-host disease and an elevated plasma total carnitine (P=0.019), and also increased plasma acyl:free carnitine ratio with veno-occlusive disease (P=0.016). Mortality was observed in those with their highest urinary total carnitine losses on day 0 (P=0.005), and in those with an abnormal day 28 plasma ratio either above or below the reference range (P=0.007). Changes in carnitine profiles were more reflective of metabolic stress and negative outcomes than of inadequate dietary intake. Associations observed direct larger studies to assess the validity of carnitine profiles as a prognostic indicator and also to assess whether prophylactic carnitine supplementation pre-HSCT could reduce mitochondrial injury and urinary losses and help mitigate inflammatory and metabolic comorbidities of HSCT.

We enrolled 150 patients in a prospective multi-center study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplant (HSCT) comparing detection of measurable residual (MRD) disease by a “Difference from Normal” flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT-1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients being screened for HSCT had detectable residual disease by ΔN (0.04–53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (0.04–14%) by ΔN. The disease free survival of this group was 10% (0–35%), compared to 55% (46–64

Osteoporotic fractures are a significant cause of morbidity in acute lymphoblastic leukemia (ALL). Our objective was to determine the incidence and predictors of fractures and recovery from osteoporosis in pediatric ALL over 6 years following glucocorticoid initiation. Vertebral fractures (VF) and vertebral body reshaping were assessed on annual spine radiographs, low-trauma non-VF were recorded at regular intervals and spine bone mineral density (BMD) was captured every 6 months for 4 years and then annually. A total of 186 children with ALL were enrolled (median age 5.3 years; range, 1.3 to 17.0 years). The cumulative fracture incidence was 32.5% for VF and 23.0% for non-VF; 39.0% of children with VF were asymptomatic. No fractures occurred in the sixth year and 71.3% of incident fractures occurred in the first 2 years. Baseline VF, cumulative glucocorticoid dose, and baseline lumbar spine (LS) BMD Z-score predicted both VF and non-VF. Vertebral body reshaping following VF was incomplete or absent in 22.7% of children. Those with residual vertebral deformity following VF were older compared to those without (median age 8.0 years at baseline [interquartile range {IQR}, 5.5 to 9.4] versus 4.8 years [IQR, 3.6 to 6.2], p = 0.04) and had more severe vertebral collapse (median maximum spinal deformity index 3.5 [IQR, 1.0 to 8.0] versus 0.5 [IQR, 0.0 to 1.0], p = 0.01). VF and low LS BMD Z-score at baseline as well as glucocorticoid exposure predicted incident VF and non-VF. Nearly 25% of children had persistent vertebral deformity following VF, more frequent in older children, and in those with more severe collapse. These results suggest the need for trials addressing interventions in the first 2 years of chemotherapy, targeting older children and children with more severe vertebral collapse, because these children are at greatest risk for incident VF and subsequent residual vertebral deformity. © 2018 American Society for Bone and Mineral Research.

Traditionally in hematopoietic stem cell transplant (HSCT), cyclosporine doses are individualized using cyclosporine trough concentrations (C0) while area under the concentration vs time curve (AUC...

Purpose Intensive multi-modal regimens have improved survival for patients with atypical teratoid rhabdoid tumor, however relapse rates remain high. A better understanding of clinical and pathologic features associated with tumor relapse is critical to risk-stratifying patients. Patients and Methods ACNS0333 treatment consisted of multi-agent chemotherapy, high-dose chemotherapy, and radiation therapy, lasting approximately 6 months. Variables including patient age, sex, tumor location, M-stage, degree of resection, order of therapy, germline status, and molecular subgroup were analyzed. Cumulative incidence (CI) of event free survival due to relapse was evaluated for each variable. Results Thirty-three of 65 evaluable patients had tumor relapse. For the entire cohort, the CI of relapse was 21.8% at 6 months, 40.6% at one year and 50.3% at 4 years. For patients with infratentorial tumors, CI of relapse was 26.3%, 34.2% and 37.2%, at 6 months, 1 and 4 years respectfully compared to 15.3%, 49.9%, and 69.7% for those with supratentorial tumors (p 0.051). Patients with SHH subtype had no relapses in the first 6 months and CI of relapse of 37.5% at 4 years, while those with TYR and MYC subgroups had CI of relapse of 33.3% and 26.7% at 6 months and 46.3% and 73.3% at 4 years respectfully (p 0.088). Patients with germline mutations had a cumulative incidence of relapse of 20% at 6 months and 60% at 12 months compared to 22.6% and 37.7% respectfully for those without. No obvious trends were noted based on other analyzed variables. Conclusions ACNS0333 was not powered to determine prognostic indicators of relapse, however, this data suggest interesting trends based on tumor location, subtype and germline status. Infratentorial location and SHH subtype maybe associated with lower risk of relapse. Larger data sets must be compiled to further investigate these variables, perform multivariate analyses and inform risk-stratification on future trials.

Children with acute myeloid leukemia (AML) are at high risk of life-threatening bacterial and fungal infection. However, little is known about the prevalence or severity of adenovirus infection in this population. Objective was to describe the characteristics, treatments and outcomes of adenovirus infection in children with newly diagnosed AML.We performed a retrospective chart review based upon 2 multicenter cohort studies that focused on identifying risk factors for infection in children with AML. Inclusion criteria were patients with de novo AML who were ≤18 years of age at diagnosis with a clinical specimen positive for adenovirus.Among the 235 patients with AML, 12 (5.1%) had positive adenovirus testing. The most common site of isolation was stool (n = 11, 91.6 %), and the most frequent symptom was diarrhea (n = 11, 91.6 %). Two patients received specific treatment for adenovirus, namely intravenous immunoglobulin only in 1 patient and both intravenous immunoglobulin and inhaled ribavirin in a second patient. In 11 patients, adenovirus resolved uneventfully without recurrence, including 10 that received no adenovirus-specific therapy. However, 1 patient developed sepsis syndrome in the setting of disseminated adenoviral infection and died from multiorgan failure.In children with AML, adenovirus infection was rare and typically not associated with severe disease, even without specific treatment. However, disseminated and fatal disease can occur in this population. Further investigations are needed to identify pediatric AML patients at particular risk for severe adenovirus infection and to determine optimal treatment approaches in these patients.

10020 Background: Low-dose metronomic topotecan (mTP) represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib (PZ) in targeting angiogenesis. This study was designed to determine the recommended phase 2 dose (RP2D) of mTP/PZ in pediatric patients with solid tumors, while describing the safety and toxicity of this regimen. Methods: A phase I dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) study of mTP/PZ was conducted at ten sites across Canada, enrolling pediatric patients aged 2-21 years with relapsed/refractory solid tumors. Patients were treated with oral mTP and PZ suspension daily without interruption in 28-day cycles, with dose escalation in accordance with the rolling-six design. Five dose levels (0.12/125, 0.16/125, 0.22/125, 0.22/160, and 0.3/160 mg/m2/day of mTP/PZ) were evaluated. PK studies were performed on day 1 and at steady state, and PD studies included circulating angiogenic factors VEGFR1, VEGFR2, VEGF, endoglin and placental growth factor. Results: Thirty patients (pts) were enrolled, of whom 26 were evaluable for dose-limiting toxicity (DLT), with median age 12 years (3-20). The most common diagnoses included osteosarcoma (8), neuroblastoma (NB, 7), Ewing sarcoma/PNET (4), and rhabdomyosarcoma (4). The most common grade 3/4 adverse events (AEs) related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphocytopenia (11%), AST elevation (11%), and lipase elevation (11%). Only 2 cycle-1 DLTs were observed on study, both at the 0.3/160 mg/m2 mTP/PZ dose level (2/5 pts) comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle-1 required treatment discontinuation. Best response was stable disease in 10/25 pts (40%) for a median duration of 6.4 months (1.7-45.1). One patient with refractory NB achieved stable disease for 45 months and continued on mTP/PZ via compassionate access after study closure. PK and PD results are pending at this time. Conclusions: The combination of oral mTP and PZ is safe and tolerable in pediatric patients with solid tumors, with a RP2D of mTP 0.22 mg/m2/day and PZ suspension 160 mg/m2/day. Ten patients achieved stable disease for a median of 6 months. The lack of objective responses suggests that this combination is likely of limited benefit for relapsed disease, but may play a role as maintenance therapy. Clinical trial information: NCT02303028.

Purpose This study aimed to estimate the burden of morbidity, in terms of health-related quality of life (HRQL), in survivors of high-risk neuroblastoma (NBL) after myeloablative chemotherapy followed by autologous hematopoietic stem cell transplant (HSCT). Patients and methods A national population-based survey was undertaken of survivors of high-risk NBL (N = 99), diagnosed between 1991 and 2010 and treated with HSCT. Parents completed a proxy questionnaire incorporating two HRQL measures, Health Utilities Index (HUI) 2 and 3. Children >12 years of age provided self-assessments. Clinical and demographic data were collected. Independent t-test and one-way analysis of variance were used to assess differences. Comparative data were obtained from previously published work and Statistics Canada's 1998 National Population Health Survey. Results On a scale of 0 (being dead) to 1.0 (perfect health), mean HRQL utility scores were 0.89 (SD = 0.11) in HUI2 and 0.84 (SD = 0.18) in HUI3. Parents reported morbidity in sensation (52.5%), pain (30.3%), cognition (28.0%), and emotion (24.2%) in HUI2 and in hearing (38.4%), pain (30.3%), cognition (27.3%), and speech (23.2%) in HUI3. HRQL was not significantly different compared to NBL survivors treated without HSCT, but was less than in nontransplanted survivors of acute lymphoblastic leukemia and Wilms tumor, and children in the general population, yet higher than in survivors of brain tumors. Conclusions HRQL is compromised in high-risk NBL survivors treated with and without HSCT. A differential effect on hearing reflects additional exposure to platinum-based chemotherapy. These results should inform long-term care and the development of new therapeutic interventions.

Adverse reactions (ARs) during the infusion of cellular therapy products (CTPs) are common in patients undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively studied pediatric patients undergoing autologous and allogeneic HSCT to determine the incidence and grade of ARs during stem cell infusion and their predictors. We analyzed data from 213 patients (120 allogeneic and 93 autologous) who received at least 1 CTP, totaling 361 infusion episodes. Serious ARs, defined as grade 2 and 3, occurred in 25 and 11% of infusions, respectively. No grade 4 or 5 ARs were noted. Independent risk factors for developing a serious AR included stem cell source (PBSC vs marrow (odds ratio (OR) 1.8, 95% confidence interval (CI): 0.4-9); cord vs marrow (OR 7.3, 95% CI: 1.3-40), overall P=0.0001) but manipulated CTPs were protective (OR 0.4, 95% CI: 0.2-0.7, P=0.004). Unlike previous adult studies, WBC and granulocyte content were not found to be risk factors in this pediatric population. These data suggest that children tolerate higher WBC content during infusion of CTPs and support the use of manipulated CTP, as indicated, to reduce the risk of adverse infusion reactions.

OBJECTIVE: To assess the effect of vertebral fractures (VF) and glucocorticoid (GC) exposure on height deficits in children during treatment of acute lymphoblastic leukemia (ALL). METHODS: Children with ALL treated without cranial radiation therapy (n = 160; median age, 5.1 years; 58.1% male) were followed prospectively for 6 years. Spinal deformity index (SDI) was used to quantify VF status. RESULTS: Baseline height z score ± SD was 0.3 ± 1.2. It fell by 0.5 ± 0.4 in the first 6 months for boys and by 0.4 ± 0.4 in the first 12 months for girls (P < 0.01 for both) and then subsequently recovered. The prevalence of VF peaked at 1 year (17.6%). Among those with VF, median SDI rose from 2 [interquartile range (IQR): 1, 7] at baseline to 8 (IQR: 1, 8) at 1 year. A mixed model for repeated measures showed that height z score declined by 0.13 (95% CI: 0.02 to 0.24; P = 0.02) for each 5-unit increase in SDI during the previous 12 months. Every 10 mg/m(2) increase in average daily GC dose (prednisone equivalent) in the previous 12 months was associated with a height z score decrement of 0.26 (95% CI: 0.20 to 0.32; P < 0.01). CONCLUSIONS: GC likely plays a major role in the observed height decline during therapy for ALL. Because only a minority of children had VF, fractures could not have contributed significantly to the height deficit in the entire cohort but may have been important among the subset with VF.

Sickle cell disease is a potentially debilitating hemoglobinopathy associated with early mortality. The only established curative therapy is hematopoietic cell transplantation (HCT) with a matched sibling donor. The National Institutes of Health nonmyeloablative regimen of alemtuzumab/300 cGy total body irradiation and prolonged sirolimus exposure for graft-versus-host disease (GVHD) prophylaxis was administered to 16 children and adolescents. Infused products were unmanipulated granulocyte colony stimulating factor mobilized peripheral blood stem cells. All patients achieved mixed donor-recipient engraftment with no cases of secondary graft failure to date. Two patients have donor myeloid chimerism in the range of 30% to 40%. No sickling crises post-HCT have been observed. Event-free and overall survival rates are 100% with median follow-up of 19.5 months. No cases of GVHD have been observed. Sirolimus weaning was possible in all but one eligible patient to date. Ongoing follow-up and a larger prospective clinical trial are required to determine the long-term safety and efficacy of this regimen in children.

Among 235 children with acute myeloid leukemia, 17 experienced 19 perianal infections. Among 12 episodes with definite abscess, 75% were severely neutropenic. Sixteen diagnostic imaging evaluations were performed; diagnostic yield was similar between computerized tomography of pelvis (5 of 10) and ultrasound (3 of 5). Consistent management approaches to perianal infection should be developed.

Little is known about the impact of enrollment on therapeutic clinical trials on adverse event rates. Primary objective was to describe the impact of clinical trial registration on sterile site microbiologically documented infection for children with newly diagnosed acute myeloid leukemia (AML). We conducted a multicenter cohort study that included children aged ≤18 years with de novo AML. Primary outcome was microbiologically documented sterile site infection. Infection rates were compared between those registered and not registered on clinical trials. Five hundred seventy-four children with AML were included of which 198 (34.5%) were registered on a therapeutic clinical trial. Overall, 400 (69.7%) had at least one sterile site microbiologically documented infection. In multiple regression, registration on clinical trials was independently associated with a higher risk of microbiologically documented sterile site infection [adjusted odds ratio (OR) 1.24, 95% confidence interval (CI) 1.01-1.53; p = 0.040] and viridans group streptococcal infection (OR 1.46, 95% CI 1.08-1.98; p = 0.015). Registration on trials was not associated with Gram-negative or invasive fungal infections. Children with newly diagnosed AML enrolled on clinical trials have a higher risk of microbiologically documented sterile site infection. This information may impact on supportive care practices in pediatric AML.

Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P

// Marc Ansari 1,2 , Patricia Huezo-Diaz Curtis 1,2,* , Chakradhara Rao S. Uppugunduri 1,2,* , Mohammed Aziz Rezgui 3 , Tiago Nava 1,3,5,6 , Vid Mlakar 1,2 , Laurence Lesne 1,2 , Yves Theoret 3,4,5 , Yves Chalandon 7 , Lee L. Dupuis 8 , Tao Schechter 8 , Imke H. Bartelink 9,17 , Jaap J. Boelens 9 , Robbert Bredius 10 , Jean-Hugues Dalle 11 , Saba Azarnoush 11 , Petr Sedlacek 12 , Victor Lewis 13 , Martin Champagne 14 , Christina Peters 15 , Henrique Bittencourt 3,4,5,16 and Maja Krajinovic 3 - 5,16,18 1 Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland 2 Department of Pediatrics, Onco-Hematology Unit, Geneva University Hospital, Geneva, Switzerland 3 Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada 4 Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada 5 Clinical Pharmacology Unit, CHU Sainte-Justine, Montreal, Quebec, Canada 6 Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil 7 Department of Medical Specialties, Division of Hematology, Geneva University Hospital, Geneva, Switzerland 8 Department of Haematology/Oncology, Blood and Marrow Transplant Unit, The Hospital for Sick Children, Toronto, Ontario, Canada 9 Pediatric Blood and Marrow Transplantation Program, University Medical Center, Utrecht, The Netherlands 10 Department of Pediatrics, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands 11 Pediatric Hematology Department, Robert Debre Hospital, Assistance Publique, Hopitaux de Paris, Paris, France 12 Department of Pediatric Hematology and Oncology Teaching Hospital, 2nd Medical School, Charles University, Prague, Czech Republic 13 Department of Pediatrics, Alberta Children’s Hospital, Calgary, Alberta, Canada 14 Department of Hematology, Hospital Verdun, Montreal, Quebec, Canada 15 Department of Pediatrics, Stem Cell Transplantation Unit, St Anna Children’s Hospital, Vienna, Austria 16 Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada 17 Department of Medicine, The University of California San Francisco, San Francisco, CA, USA 18 On Behalf of the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, Leiden, The Netherlands * These authors have contributed equally to this work Correspondence to: Patricia Huezo-Diaz Curtis, email: // Keywords : busulfan, pharmacokinetics, pharmacogenetics, toxicity, hematopoietic stem cell transplantion Received : July 18, 2017 Accepted : July 23, 2017 Published : August 27, 2017 Abstract Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 ( GSTA1 ) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p

Severe steroid-refractory acute graft-versus-host disease (aGVHD) is related to significant mortality and morbidity after allogeneic stem cell transplantation. Early clinical trials of therapy with human mesenchymal stem cells (hMSCs) in pediatric patients with severe aGVHD resistant to multiple immunosuppressive agents showed promising results. In this study, we evaluated the risk/benefit profile of remestemcel-L (Prochymal), a third-party, off-the-shelf source of hMSCs, as a rescue agent for treatment-resistant aGVHD in pediatric patients. Children with grade B-D aGVHD failing steroids and, in most cases, other immunosuppressive agents were eligible for enrollment. Patients received 8 biweekly i.v. infusions of 2 × 106 hMSCs/kg for 4 weeks, with an additional 4 weekly infusions after day +28 for patients who achieved either a partial or mixed response. The enrolled patients compose a very challenging population with severe disease that was nonresponsive to the standard of care, with 88% of the patients experiencing severe aGVHD (grade C or D). Seventy-five patients (median age, 8 yr; 58.7% male; and 61.3% Caucasian) were treated in this study. Sixty-four patients (85.3%) had received an unrelated hematopoietic stem cell graft, and 28 patients (37.3%) had received a cord blood graft. At baseline, the distribution of aGVHD grades B, C, and D was 12.0%, 28.0%, and 60.0%, respectively. The median duration of aGVHD before enrollment was 30 d (range, 2 to 1639 d), and patients failed a median of 3 immunosuppressive agents. Organ involvement at baseline was 86.7% gastrointestinal, 54.7% skin, and 36.0% liver. Thirty-six patients (48.0%) had 2 organs involved, and 11 patients (14.7%) had all 3 organs involved. When stratified by aGVHD grade at baseline, the rate of overall response (complete and partial response) at day +28 was 66.7% for aGVHD grade B, 76.2% for grade C, and 53.3% for grade D. Overall response for individual organs at day +28 was 58.5% for the gastrointestinal system, 75.6% for skin, and 44.4% for liver. Collectively, overall response at day +28 for patients treated for severe refractory aGVHD was 61.3%, and this response was correlated with statistically significant improved survival at day +100 after hMSC infusion. Patients who responded to therapy by day +28 had a higher Kaplan-Meier estimated probability of 100-d survival compared with patients who did not respond (78.1% versus 31.0%; P

Introduction: In children diagnosed with leukemia, relapse and its associated morbidity and mortality remain the most dreaded consequences of the disease. Therefore, the discovery and implementation of novel and broadly applicable therapeutic strategies for these patients are urgently needed. Currently, a number of precision therapeutic approaches have been formulated where molecular analyses of the malignant cells have been used to inform, often multiple, probable targets and potential therapeutic agents. However, a common drawback of this approach has been the uncertainty involved in selecting the drug with the most and clinically relevant cytotoxic potential. In vitro xenograft approaches, although can provide key information on drug activity and side effects, are time consuming and impractical and cumbersome in most cases. We have recently demonstrated the ability of a bone marrow stromal derived cell line to sustain the growth and survival of patient leukemic cells in culture that has allowed in vitro evaluations of drug response.This methodology was combined with a previously validated molecular pathway analysis program to identify effective agents or combinations for a subsequent informed precision clinical trial. Methods: Gene expression profiles from refractory pediatric leukemic cells were analyzed against similar data from more than 12, 000 tumors and outlier analyses were carried out to generate a list of overexpressed genes. This information was computed to identify hypothetically activated pathways, druggable targets and potential agents from a panel of FDA approved drugs. A bone marrow stromal cell line was established and characterized that has been shown to support leukemia cell proliferation in vitro. Briefly, stromal cells were co-cultured with leukemic cells at pre-determined ratios with and without the drugs identified in the genomic analysis. After four days in culture, leukemic cells were re-suspended and analyzed for proliferation. Target modulation and activated cell death pathways were queried by Western blot analyses. Results: Multiple targets and potential agents for effective therapeutics were identified against an initial set of relapsed leukemia specimens. For example, in patient # P700491 (pre B-ALL) gene expression data sets revealed clustering within the area of ALL and AML in the reference cancer genomics data. Comparative tumor RNA seq outlier analysis showed molecular abnormalities in BTK, JAK3 and PIK3CD, corresponding to molecular categories of RTK, JAK-SAT and PI3K-AKT-mTOR pathways targetable by the drugs Ibrutinib, WHI-P131 and Idelalisib, respectively. However, in vitro studies showed significant cell killing with Idelalisib and not with the other two agents. Target modulation assays showed effective induction of apoptosis including PARP cleavage in Idelalisib treated leukemia cells compared to controls, indicating the feasibility of this approach to effectively identify potentially applicable agents for this individual patient. Conclusions: We demonstrate the ability of a newly cloned bone marrow stromal derived cell line to sustain the growth and survival of patient leukemic cells in culture that has allowed in vitro target modulation and target validation analyses for cytotoxicity. This methodology was combined with a previously demonstrated molecular pathway interrogation program to ascertain effective agents or combinations for an experimentally informed precision clinical trial. Importantly, our data showed that genomically identified actionable targets are not universally predictive of tumor response and an in vitro cytotoxicity analysis step may enhance the accuracy of this approach. We describe the practical advantages and versatility of this work-flow to inform the selection of agents in future umbrella trials. It is anticipated that the information obtained will lead to an applicable clinical trial the near future. Disclosures Narendran: Bayer: Honoraria, Other: CANTRK Advisory Board .

Introduction Chronic graft versus host disease is the major cause of poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Clinically significant moderate-severe chronic GvHD (cGvHD) rarely shows a sustained complete response to immunosuppressive drugs and non-responders either die or suffer long-term. Early and accurate prediction of ensuing cGvHD can help identify high risk patients to make preemptive treatment possible. In the present study, we retrospectively analyzed the transcriptome of immunity related genes at one month post-transplant with the aim to identify a potential early and accurate predictor of clinically significant cGvHD. Methods An adult retrospective cohort of 73 human leukocyte antigen (HLA) matched myeloablative allogeneic HCT recipients were included. All patients received 4.5 mg/kg antithymocyte globulin as GvHD prophylaxis. Diagnosis of cGvHD was based on National Institutes of Health consensus criteria with the median day of diagnosis being 126 days. Total RNA extracted from cryopreserved peripheral blood mononuclear cells at one month post-transplant was used to run a gene expression CodeSet profiling of 594 immunity related genes including 15 internal reference genes using Nanostring Technology. Benjamini Hochberg procedure was used to calculate the P value and the false discovery rate (FDR) of differentially expressed genes. Results A set of 12 differentially expressed genes with a Benjamini Hochberg P-value (BHP) of 7 in this panel of 12 genes was able identify patients with high risk of developing mod-severe cGVHD with a sensitivity of 79% and specificity of 88% (AUC = 0.88, P Conclusion The robust and rapid technique of Nanostring based transcriptome profiling identified a gene panel consisting of 12 genes for an early prediction of moderate-severe cGVHD (one month) with high sensitivity and specificity. A precision medicine approach of preemptive treatment of cGVHD can be possible using this study leading to improved outcomes of HCT.

International audience; The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT.

BACKGROUND The prevalence and severity of Clostridium difficile infection (CDI) has increased over time in adult patients, but little is known about CDI in pediatric cancer. The primary objectives were to describe the incidence and characteristics of CDI in children with de novo acute myeloid leukemia (AML). The secondary objective was to describe factors associated with CDI. METHOD We performed a multicenter, retrospective cohort study of children with de novo AML and evaluated CDI. Recurrence, sepsis and infection-related death were examined. Factors associated with CDI were also evaluated. RESULTS Forty-three CDI occurred in 37 of 341 (10.9%) patients during 42 of 1277 (3.3%) courses of chemotherapy. There were 6 children with multiple episodes of CDI. Three infections were associated with sepsis, and no children died of CDI. Only 2 children had an associated enterocolitis. Both days of broad-spectrum antibiotics (odds ratio 1.03, 95% confidence interval: 1.01 to 1.06; P = 0.003) and at least 1 microbiologically documented sterile site infection (odds ratio 10.81, 95% confidence interval: 5.88 to 19.89; P < 0.0001) were independently associated with CDI. CONCLUSIONS CDI occurred in 11% of children receiving intensive chemotherapy for AML, and outcomes were not severe. CDI is not a prominent issue in pediatric AML in terms of prevalence, incidence or associated outcomes.

Summary Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in paediatric acute myeloid leukaemia (AML). This study describes risk factors for IFI and IFI-related sepsis in this population. We conducted a population-based, retrospective cohort study of children with AML in Canada. IFIs during chemotherapy and prior to haematopoietic stem cell transplantation, relapse, persistent disease or death were identified. Risk factors for proven or probable IFI were examined. Among courses complicated by IFI, risk factors for sepsis were also evaluated. There were 341 children with AML included of which 41 (12.0%) experienced 46 different episodes of IFI. Candida species accounted for 23 (50.0%) of IFIs and Aspergillus spp. accounted for 14 (30.4%). Days of broad-spectrum antibiotics, days of corticosteroids and neutropenia at start of the course were independently associated with IFI. Only days of fever were independently associated with IFI-related sepsis. Invasive fungal infections occurred in 12.0% of paediatric AML patients. Risk factors for IFI and IFI-related sepsis were identified. This knowledge may help to consider targeted strategies.

Although the role of autologous hematopoietic cell transplantation (auto-HCT) is well established in neuroblastoma (NBL), the role of allogeneic HCT (allo-HCT) is controversial. The Center for International Blood and Marrow Transplant Research conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto-HCT (n=46 and 97, respectively). One-year and five-year OS were 59% and 29% for Group 1 and 50% and 7% for Group 2, respectively. Among donor types, disease-free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not at 5 years post HCT. Patients in CR or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared with those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared with those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.

Acute lymphoblastic leukemia (ALL) is one of the most prevelant pediatric malignancies. Although cure rates have improved in recent decades, approximately one in five children relapse, and survival rates post-relapse remain low. Therefore, more effective and innovative therapeutic strategies are needed in order to improve the outcome in these children. Aurora kinases, a family of serine/threonine kinases essential for regulated mitosis, are overexpressed in many forms of cancer, and have been identified as potential targets for cancer therapeutics. Based on this premise, we evaluated the activity of the Aurora-A/B inhibitor AT9283 against pediatric leukemia cells. It was found that AT9283 significantly inhibited the growth and survival of cell lines derived from patients with pediatric leukemia. Specifically, AT9283 promoted Flt-3 dephosphorylation, inhibiting the activity of downstream effectors such as Erk and Mek. In addition, apoptotic markers were also identified, providing a panel of markers for biological correlative analysis for drug activity. Lastly, drug combination studies demonstrated the potential of several novel and conventional agents to synergize with AT9283, including apicidin, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and doxorubicin. These data provide a rationale for further studies and the formulation of a clinical trial of AT9283 for the treatment of refractory pediatric ALL.

Rothia spp. (previously termed Stomatococcus) are normal flora that can cause invasive infections in immunocompromised hosts. The objective of this study was to describe infection characteristics and outcomes of Rothia spp. infections in a large cohort of children with newly diagnosed acute myeloid leukemia (AML). This retrospective chart review is a subanalysis of a larger study in which the aim was to identify factors associated with infection in pediatric patients with AML. Only sterile site infections occurring during chemotherapy were included. Among 578 children with AML, 17 (2.9%) children with at least 1 Rothia spp. infection were identified. All children were neutropenic at the time of infection. Eight (47%) had antecedent colitis or mucositis. Of the 17 infections, 16 were bacteremia and 1 was meningitis. Sepsis occurred in 4 patients, and 1 patient died due to infection. Rothia spp. infections are rare in pediatric AML but can cause significant morbidity and mortality. Future studies should describe trends in incidence and resistance patterns over time.

Purpose Vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been reported. Patient and Methods We prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semiquantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain, and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures. Results Of the 155 children, 25 (16%; 95% CI, 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen (52%) of the 25 children with incident vertebral fractures also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI, 2.3 to 23.1; P = .001). In addition, for every one standard deviation reduction in spine BMD Z-score at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI, 1.2 to 2.7; P = .006). Conclusion Children with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features.

To determine whether in vivo T-cell depletion, which lowers GVHD, abrogates the antileukemic benefits of myeloablative total body irradiation–based conditioning and unrelated donor transplantation, in the present study, we analyzed 715 children with acute lymphoblastic leukemia. Patients were grouped for analysis according to whether conditioning included antithymocyte globulin (ATG; n = 191) or alemtuzumab (n = 132) and no in vivo T-cell depletion (n = 392). The median follow-up time was 3.5 years for the ATG group and 5 years for the alemtuzumab and T cell–replete groups. Using Cox regression analysis, we compared transplantation outcomes between groups. Compared with no T-cell depletion, grade 2-4 acute and chronic GVHD rates were significantly lower after in vivo T-cell depletion with ATG (relative risk [RR] = 0.66; P = .005 and RR = 0.55; P < .0001, respectively) or alemtuzumab (RR = 0.09; P < .003 and RR = 0.21; P < .0001, respectively). Despite lower GVHD rates after in vivo T-cell depletion, nonrelapse mortality, relapse, overall survival, and leukemia-free survival (LFS) did not differ significantly among the treatment groups. The 3-year probabilities of LFS after ATG-containing, alemtuzumab-containing, and T cell–replete transplantations were 43%, 49%, and 46%, respectively. These data suggest that in vivo T-cell depletion lowers GVHD without compromising LFS among children with acute lymphoblastic leukemia who are undergoing unrelated donor transplantation with myeloablative total body irradiation–based regimens.

Hodgkin lymphoma (HL) is cured in the majority of children and adolescents. However, there remains a group of patients with primary refractory or relapsed disease for whom cure is more difficult to achieve. Most of these patients receive high-dose chemotherapy followed by auto-SCT, with expected cure rates ranging from 40 to 60%. Conditioning regimens often consist of multiple non-cross-resistant agents, with well-described risks of morbidity and mortality. The use of single-agent high-dose melphalan (HDM) as conditioning, before autologous rescue, has been described in adult patients at our center, with comparable efficacy and less morbidity. We present a series of eight pediatric patients conditioned with single-agent HDM before autologous stem cell rescue for relapsed and primary refractory HL. All patients engrafted with a median of 12 days to neutrophil engraftment. Two patients subsequently relapsed. Seven patients are currently alive, and seven of eight patients have no evidence of disease (one in CR3). Toxicities included grade 4 hematologic in 8/8, grade 3 mucositis in 3/8, grade 3 infectious in 2/8 and grade 4 infectious in 1/8. Our analysis suggests that this regimen is feasible in pediatric patients with acceptable engraftment and toxicity.