Chemotherapy In Pediatric Patients Research Articles

Phase II Study of Midostaurin + Chemotherapy in Pediatric Patients with Untreated, Newly Diagnosed, FLT3-Mutated Acute Myeloid Leukemia (AML)

Background: In pediatric patients with AML, the presence of FLT3-internal tandem duplication (ITD) mutation is indicative of high-risk disease and confers a worse prognosis and a greater chance of relapse. Midostaurin is a multikinase inhibitor with potent activity against both mutated and non-mutated FLT3. In adult patients with FLT3-mutated AML, midostaurin in combination with chemotherapy has demonstrated good safety/tolerability and significantly improved overall survival (OS) and event-free survival (EFS) compared with placebo + chemotherapy. We present here the design of an ongoing phase II study (NCT03591510) evaluating midostaurin combined with standard chemotherapy and as a single-agent post-consolidation therapy in newly diagnosed pediatric patients with FLT3-mutated AML, other than acute promyelocytic leukemia. Study Design and Methods: This open-label, single-arm study is composed of 2 parts. For Part 1, the primary objective is to determine the recommended phase II dose (RP2D) of midostaurin in combination with chemotherapy, as determined by the occurrence of dose-limiting toxicities. For Part 2, in which patients will receive the RP2D of midostaurin, the primary objective is to evaluate the efficacy of midostaurin + chemotherapy as measured by the EFS rate at 24 mo (for regulatory purposes outside the US) or to assess the safety/tolerability of midostaurin + chemotherapy (for regulatory purposes within the US). Secondary objectives include safety/tolerability (outside US) and EFS at 24 mo (within US), other efficacy parameters (including OS, complete remission [CR], CR with incomplete blood count recovery [CRi], cumulative incidence of relapse, and minimal residual disease-negative status), and characterization of the pharmacokinetics of midostaurin. Eligible patients are aged 3 mo to < 18 yr with expected survival of > 12 wk, have a Lansky or Karnofsky performance status of ≥ 60, and have previously untreated de novo AML with FLT3 mutation: ITD and/or mutation in the tyrosine kinase domain, with mutant/wild-type signal ratio cutoff of ≥ 0.05. Exclusion criteria include any concurrent malignancy, Philadelphia chromosome or BCR-ABL1-positive AML, AML associated with Down syndrome, secondary AML, symptomatic leukemic central nervous system involvement, bone marrow failure syndrome, or prior treatment with a FLT3 inhibitor. Patients are to receive 5 treatment blocks: 2 of standard induction (Blocks 1-2) and 3 of consolidation (Blocks 3-5) chemotherapy, each with sequential twice-daily (BID) oral midostaurin. In Part 1 of the study, midostaurin will be given at a starting dose of 30 mg/m2 BID; dose escalation and determination of RP2D will be facilitated by a Bayesian hierarchical logistic regression model guided by escalation with overdose control principle. In Part 2, midostaurin will be administered at the RP2D. Induction therapy will be the local standard chemotherapy regimen with midostaurin starting after 24 hr from identification of FLT3 abnormalities and continuing for 14 d for Block 1, and FLADx (fludarabine + high-dose cytarabine on D1-5, daunorubicin on D2, 4, 6) with sequential midostaurin on D8-21 for Block 2. Patients demonstrating CR or modified CRi will proceed to consolidation with the following chemotherapy regimens, each with sequential midostaurin on D8-21: HAM (high-dose cytarabine on D1-3, mitoxantrone on D3, 4) for Block 3, HA3E (high-dose cytarabine on D1-3, etoposide on D1-5) for Block 4, and HiDAC (high-dose cytarabine on D1-3) for Block 5. Patients must be in continued remission (CR or modified CRi) to receive each block of consolidation therapy. Patients who complete Block 5 and remain in remission will proceed to 12 × 28-d cycles of post-consolidation therapy with single-agent midostaurin. Patients may undergo allogeneic hematopoietic stem cell transplantation at any time at the investigator's discretion. Overall, the aim is to recruit a minimum of 52 patients, including at least 49 at the RP2D dose. This study is currently enrolling patients at 13 centers in 7 countries (as of July 26, 2019), and a total of 37 centers in 14 countries are planned. Disclosures Reinhardt: Novartis: Other: Participation in Advisory Boards; Jazz: Other: Participation in Advisory Boards, Research Funding; CSL Behring: Research Funding; Roche: Research Funding. Zwaan:BMS: Research Funding; Servier: Consultancy; Sanofi: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Roche: Consultancy; Incyte: Consultancy. Hoenekopp:Novartis Pharma AG Basel: Employment, Equity Ownership. Niolat:Novartis Pharma: Employment. Ifrah:Novartis: Employment. Noel-Baron:Novartis: Employment, Equity Ownership. Locatelli:Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BluebirdBio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Midostaurin is a kinase inhibitor approved in combination with chemotherapy for the treatment of FLT3-mutated AML in adults; the study reported here is in pediatric patients with FLT3-mutated AML.

Xiyanping Plus Azithromycin Chemotherapy in Pediatric Patients with Mycoplasma pneumoniae Pneumonia: A Systematic Review and Meta-Analysis of Efficacy and Safety.

Background Xiyanping injection (XYP) is a well-known Chinese medicinal preparation reputed as a most effective alternative to antibiotics. XYP has been widely used in combination therapies to treat various infectious diseases, among which XYP plus azithromycin (AZM) chemotherapy is often used for the treatment of Mycoplasma pneumoniae pneumonia in pediatric patients (p-MPP) in China. Objective The present study just aimed to confirm whether XYP can improve the clinical efficacy and safety of AZM chemotherapy for p-MPP by performing meta-analysis and systematic review. Methods A meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The randomized controlled trials (RCTs) concerning XYP plus AZM chemotherapy for p-MPP were selected, for which the main outcomes included overall response rate (ORR), antipyretic time, cough disappearance time, lung wet Rales disappearance time, hospitalization duration, and adverse drug reactions (ADRs). Based on the data extracted, the meta-analysis was conducted by using a standard data extraction form. Results Nine RCTs involving 963 patients were included for meta-analysis. More concretely, the combination therapy showed the risk ratio (RR) and 95% confidence intervals (CI) of ORR and ADRs as (RR, 1.21 [95% CI, 1.15, 1.28]) and (RR, 0.37 [95% CI, 0.27, 0.51]), respectively. And other major outcomes were as follows: hospitalization durations (standard mean difference (SMD), −1.32 [95% CI, −1.48, −1.16]), antipyretic time (SMD, −1.26 [95% CI, −1.70, −0.83]), cough disappearance time (SMD, −1.07 [95% CI, −1.38, −0.75]), and the disappearance time of lung wet Rales (SMD, −0.83 [95% CI, −1.07, −0.60]). With statistically significant differences in various aspects, the combination therapy plus XYP displayed obvious advantages in contrast to AZM alone. Conclusion Overall, XYP might reduce the incidence of ADRs and significantly improve the clinical efficacy for p-MPP receiving AZM chemotherapy.

Chemotherapy-induced nausea and vomiting control in pediatric patients receiving ifosfamide plus etoposide: a prospective, observational study.

Little evidence exists regarding the emetogenicity of chemotherapy in pediatric patients. This study describes the prevalence of chemotherapy-induced nausea and vomiting (CINV) in pediatric patients receiving etoposide plus ifosfamide over 5days, a common pediatric regimen. English-speaking, non-chemotherapy-naïve patients aged 4 to 18years about to receive etoposide 100mg/m2/day plus ifosfamide 1800mg/m2/day over 5days participated. Antiemetic prophylaxis was determined by each patient's care team. Emetic episodes were recorded and nausea severity was assessed by patients beginning with the first chemotherapy dose, continuing until 24h after the last chemotherapy dose (acute phase) and ending 7days later (delayed phase). The proportion of patients experiencing complete acute CINV control (no nausea, no vomiting, and no retching), the primary study endpoint, was described. The prevalence of complete chemotherapy-induced vomiting (CIV) and chemotherapy-induced nausea (CIN) during the acute, delayed, and overall (acute plus delayed) phases; complete delayed and overall CINV control; and anticipatory CINV were also determined. Twenty-four patients participated; acute CINV was evaluable in 22. Most (75%; 18/24) received a 5-HT3 antagonist plus dexamethasone for antiemetic prophylaxis. Few (23%; 5/22) experienced complete acute CINV control. Complete acute CIV and CIN control were experienced by 57% (13/23) and 27% (6/22) of patients, respectively. Complete delayed CINV, CIV, and CIN control rates were 42% (8/19), 70% (14/20), and 42% (8/19), respectively. Our findings support the classification of etoposide 100mg/m2/day plus ifosfamide 1800mg/m2/day IV over 5days as highly emetogenic. This information will optimize antiemetic prophylaxis selection and CINV control in pediatric patients.

Hemophagocytic Lymphohistiocytosis Secondary to Malignancy and Chemotherapy in Pediatric Patients: A Single-Institution Experience

AbstractHemophagocytic lymphohistiocytosis (HLH) is an uncommon yet potentially devastating systemic disease, arising from uncontrolled activation of the immune system. While the primary form of this disease can be caused by genetic mutation(s), the secondary form may be triggered by infection and hematologic, malignant, and metabolic conditions. The diagnosis of HLH remains a clinical challenge due to nonspecific symptoms. Proper diagnosis is significantly more difficult among patients with acute leukemia who have received chemotherapy. The objective of this study is to describe three unique cases of secondary HLH, describe the specific treatment, and improve the awareness of this condition. Two patients with acute myeloid leukemia (AML) and one with acute lymphoblastic leukemia were diagnosed with HLH, having fulfilled the criteria as outlined in the HLH-2004 protocol. They then received HLH-specific treatment. Two patients passed – one from refractory HLH and one from primary disease (i.e., AML) – and one patient remains alive 22 months after her allogeneic bone marrow transplant. The diagnosis of HLH requires the presence of any five of the eight criteria. Due to its heterogeneous presentation, it remains imperative that treating clinicians remain cognizant about HLH so that prompt diagnosis may allow appropriate treatment.

Classification of the acute emetogenicity of chemotherapy in pediatric patients: A clinical practice guideline.

This clinical practice guideline (CPG) provides clinicians with recommendations regarding chemotherapy emetogenicity classification in pediatric oncology patients. This information is critically important for the appropriate selection of antiemetic prophylaxis. Recommendations are based on a systematic review limited to pediatric patients and a framework for classification when antiemetic prophylaxis is provided. Findings of 87 publications informed the emetogenicity classification of 49 single-agent and 13 combination-agent regimens. Information required for the classification of many chemotherapies commonly administered to pediatric patients is lacking. In the absence of pediatric data, consultation of methodologically sound CPGs aimed at adult oncology patients may be appropriate.

Increased 18F-FDG accumulation in the tonsils after chemotherapy for pediatric lymphoma: a common physiological phenomenon.

Increased 18F-fluorodeoxyglucose (FDG) uptake in the tonsils after the completion of chemotherapy in patients with lymphoma may be misdiagnosed as tumor recurrence. This study aimed to investigate the changes in physiological FDG uptake in the tonsils during and after chemotherapy in pediatric patients with lymphoma. A total of 47 FDG-PET/CT scans acquired from 13 pediatric patients with lymphoma (before chemotherapy [preC] = 9; during chemotherapy [durC] = 12; within 1 month after the end of chemotherapy [endC] = 11; and after achieving complete response [postC] = 15) were retrospectively included in this study. FDG uptake in the palatine tonsils was assessed using maximum standardized uptake value (SUVmax). The relative size of the palatine tonsils was calculated as the tonsil-pharyngeal ratio (TPR). Serial changes in the SUVmax and TPR were evaluated. The mean SUVmax was 3.7 ± 1.7, 2.6 ± 0.7, 2.3 ± 0.8, and 6.2 ± 1.6, at the preC, durC, endC, and postC scans, respectively (p < 0.0001); TPR was 59.0 ± 11.2%, 58.3 ± 9.4%, 54.4 ± 7.9%, and 62.2 ± 12.0% in these groups, respectively, with no significant inter-group differences. TPR and SUVmax showed no correlation. Increased physiological FDG uptake in the tonsils is commonly observed after the completion of chemotherapy, even in the absence of reactive hypertrophy.

Significant effect of infection and food intake on sirolimus pharmacokinetics and exposure in pediatric patients with acute lymphoblastic leukemia

BackgroundSirolimus is increasingly investigated as a new targeted therapy in pediatric populations. To date, population pharmacokinetic (PK) studies have identified several factors that explain in part the large between-patient variability in sirolimus PK. However, within-patient variability in sirolimus PK is not well documented. This study presents examples of model-based PK-guided dosing of sirolimus in children with acute lymphoblastic leukemia (ALL), where patients experienced significant changes in sirolimus blood concentrations due to infection and food intake during the treatment period. MethodsClinical PK data were obtained as part of a prospective pilot study of sirolimus combined with multiagent chemotherapy in pediatric patients with ALL (ClinicalTrial.gov identifier: NCT01658007). A PK model-informed loading dose of 1.8 mg/m2 every 8 h was started on the first day of sirolimus treatment. Subsequent doses were adjusted based on concentration measurements the first blood draw scheduled 24 h into the regimen on the morning of day 2. Sirolimus blood concentrations were determined by a validated LC-MS/MS assay. All dosing recommendations were generated in real time using the PK model with Bayesian estimation. ResultsThree patients were enrolled in this study. Two patients achieved target concentration attainment with the PK model-informed loading dose on day 1 of sirolimus treatment. Subsequent unexpected high sirolimus concentrations were observed in two patients, where patients had flulike symptoms such as fever and cough. A sudden decrease in sirolimus concentrations was observed in one patient after switching sirolimus administration from the fed to the fasting state. ConclusionsThis study highlights within-patient fluctuations in sirolimus concentrations associated with intercurrent infection and with changes in diet. These findings highlight the challenge of maintaining a target sirolimus concentration as a patient's clinical status changes, and the benefit of intensive monitoring of therapeutic drug levels in children treated with sirolimus. Intra-patient alternations in sirolimus PK due to similar disease/food interactions may be relevant in pediatric patients treated with sirolimus for other disease indications.

Obesity in pediatric patients with acute lymphoblastic leukemia increases the risk of adverse events during pre-maintenance chemotherapy.

Obesity correlates with adverse events (AEs) in children with acute myelogenous leukemia and during maintenance therapy for acute lymphoblastic leukemia (ALL). Less is known about AEs in obese ALL patients during pre-maintenance chemotherapy. We evaluated the relationship between obesity (body mass index (BMI) ≥ 95th percentile) and AEs during pre-maintenance chemotherapy in pediatric patients with ALL. One hundred fifty-five pediatric ALL patients diagnosed at a single institution between 2006 and 2012 were retrospectively evaluated for infections, treatment-requiring hypertension, insulin-requiring hyperglycemia, pancreatitis, pediatric intensive care unit admissions, sepsis, febrile neutropenia (FN) admissions, thrombosis, hepatotoxicity, and nephrotoxicity. Univariate and multivariable analyses compared proportions of obese versus nonobese patients experiencing AEs. AEs occurring significantly more frequently in obese patients by univariate analysis included treatment-requiring hypertension (17.5% vs 6.1%; OR, 3.27; 95% CI, 1.1-10.0, P=0.0497) and insulin-requiring hyperglycemia (25.0% vs 11.3%; OR, 2.62; 95% CI, 1.04-6.56, P=0.04). Obese patients had greater incidence rates for recurrent admission-requiring infections (incidence rate ratio (IRR) 1.64; 95% CI, 1.08-2.48, P=0.02) and recurrent FN admissions (IRR, 1.53; 95% CI, 1.10-2.12, P=0.01). Accounting for combined age and NCI risk status, obesity was a risk factor for treatment-requiring hypertension (OR, 3.90; 95% CI, 1.19-12.76, P=0.02), insulin-requiring hyperglycemia (OR, 3.92; 95% CI, 1.39-11.05, P=0.01), and FN admission (OR, 2.92; 95% CI, 1.27-6.73, P=0.01). During pre-maintenance chemotherapy for ALL, obesity is a risk factor for the development of hypertension, hyperglycemia, and FN admissions. This research provides implications for augmented preventive and supportive care guidelines in obese ALL patients.

Dose Optimization Based on Population Pharmacokinetic Modeling of High-Dose Cyclosporine, a P-glycoprotein Inhibitor, in Combination with Systemic Chemotherapy in Pediatric Patients with Retinoblastoma.

Retinoblastoma is a childhood malignancy of the retina. To increase the exposures of systemic chemotherapy, high-dose cyclosporine, as a P-glycoprotein modulating agent, has been combined with a standard chemotherapy. However, the effective and safe dose of cyclosporine has not been well evaluated. This study is to optimize cyclosporine dose using population pharmacokinetic modeling. Clinical data were obtained from 161 systemic chemotherapy cycles of 34 pediatric retinoblastoma patients between December 2006 and April 2015. Total 15 scenarios were simulated by 5 different doses (12, 14, 15, 17, and 20 mg/kg) of cyclosporine in 3 different weight groups (5-10, 10-15, and 15-20 kg). Numerical success ratio was obtained after assessing the simulated target cyclosporine concentration in the range of 2,000-2,500 ng/mL using NONMEM version 7.3 software. A final model was built based on a 1-compartment model with weight-normalized allometric scaling to minimize the variability of pediatric size. In simulations, numeric success ratio with 15 mg/kg/day and the above were higher than that of traditional doses in all of the scenario groups. No significant adverse responses were reported. Conclusion and Relevance: High-dose cyclosporine regimen as a P-gp modulator is required to improve the efficacy of systemic chemotherapy with caution in pediatric patients with retinoblastoma. Clearance, volume of distribution, and body weight are important parameters to consider in selecting adequate dosing regimen.

Thyroid dysfunction in patients with childhood-onset medulloblastoma or primitive neuroectodermal tumor.

Purpose We investigated the clinical characteristics of patients who developed thyroid dysfunction and evaluated the risk factors for hypothyroidism following radiotherapy and chemotherapy in pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET).Methods The medical records of 66 patients (42 males) treated for medulloblastoma (n=56) or PNET (n=10) in childhood between January 2000 and December 2014 at Seoul National University Children’s Hospital were retrospectively reviewed. A total of 21 patients (18 high-risk medulloblastoma and 3 PNET) underwent high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR)Results During the median 7.6 years of follow-up, 49 patients (74%) developed transient (n=12) or permanent (n=37) hypothyroidism at a median 3.8 years of follow-up (2.9–4.6 years). Younger age (<5 years) at radiation exposure (P=0.014 vs. ≥9 years) and HDCT (P=0.042) were significantly predictive for hypothyroidism based on log-rank test. However, sex, type of tumor, and dose of craniospinal irradiation (less vs. more than 23.4 Gy) were not significant predictors. Cox proportional hazard model showed that both younger age (<5 years) at radiation exposure (hazard ratio [HR], 3.1; vs. ≥9 years; P=0.004) and HDCT (HR, 2.4; P=0.010) were significant predictors of hypothyroidism.Conclusions Three-quarters of patients with pediatric medulloblastoma or PNET showed thyroid dysfunction, and over half had permanent thyroid dysfunction. Thus, frequent monitoring of thyroid function is mandatory in all patients treated for medulloblastoma or PNET, especially, in very young patients and/or high-risk patients recommended for HDCT/ASCR.

Experience of C5V basic regmints as neoadjuvant chemotherapy in pediatric patients with hepatoblastoma

目的 观察C5V方案为基础的新辅助治疗在儿童肝母细胞瘤的临床疗效。 方法 回顾性分析中国医科大学附属盛京医院肿瘤科收治的8例诊断为肝母细胞瘤并且应用C5V为基础新辅助化疗方案的临床资料，并进行随访，总结其临床疗效。 结果 8例患儿皆存活，7例患儿得到根治性手术，1例患儿耐药，C5V方案新辅助治疗有效率达87.5%。不良反应方面：腹痛发生率37.8%，恶心呕吐发生率32.4%，骨髓抑制发生率24.3%，肝功能异常发生率5.4%，其中Ⅲ/Ⅳ级骨髓毒性发生率为0.81%，未发现Ⅲ/Ⅳ级其他不良反应。 结论 儿童肝母细胞瘤能否完全手术切除是其获得长期缓解的关键，新辅助化疗有助于降低儿童肝母细胞瘤的分期，提高手术切除率，从而提高生存率。

Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL

AbstractEarly response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of IGH and TRG genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children's Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC.

CA180-372: An International Collaborative Phase 2 Trial of Dasatinib and Chemotherapy in Pediatric Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

▪Introduction: Ph+ ALL comprises ~5% of childhood and adolescent ALL. Prior to development of tyrosine kinase inhibitor (TKI) therapy, survival rates were poor. Less than half of patients (pts) survived despite treatment with intensive chemotherapy and frequent use of allogeneic hematopoietic stem cell transplant (HSCT) in first remission (CR1). The Children's Oncology Group (COG) AALL0031 trial (Schultz, JCO 2009) and the EsPhALL trial (Biondi, Lancet Oncology 2012) showed adding imatinib to different intensive chemotherapy backbones improved event-free (EFS) and overall survival (OS) in pediatric Ph+ ALL. Dasatinib is attractive to study in Ph+ ALL because it is a dual ABL/SRC TKI that is 300 times more potent than imatinib in vitro, is active against most ABL1 TKI domain mutations that cause imatinib resistance, and accumulates in the central nervous system (CNS), a sanctuary site for ALL where imatinib penetration is poor.Methods: We conducted a phase 2 trial of dasatinib added to the EsPhALL chemotherapy backbone in pediatric (>1-17.99 years (yrs) of age) Ph+ ALL pts at COG sites in North America and Australia and EsPhALL sites in Italy and the United Kingdom. Protocol therapy added continuous daily dasatinib (60 mg/m2) at day 15 of induction chemotherapy. The study measured minimal residual disease (MRD) by Ig/TCR PCR, flow cytometry, and BCR - ABL1 RT-PCR, with clinical actions based upon a single method, in this hierarchical order. Pts with MRD ≥ 0.05% at the end of block Ib (day 78) and those with MRD 0.005-0.05% at end of Ib who remained MRD positive at any detectable level after three additional high-risk (HR) chemotherapy blocks underwent HSCT in CR1. Dasatinib treatment post HSCT was optional. The remaining pts received chemotherapy plus daily dasatinib for 2 yrs, with cranial irradiation limited to CNS3 pts. The primary study endpoint was 3-year EFS assessed when all patients completed 3 years of follow-up.Results: From April 2012 to May 2014, 109 pts enrolled; 3 did not meet inclusion criteria and received no trial therapy. The median age was 9.0 yrs (range 1-17), 54% were males, and 80% were Caucasian. 71% had CNS1 status at baseline, 24% CNS2, and 5% CNS3. Safety analysis included all treated pts (N=106) and efficacy analysis included all treated Ph+ ALL pts (N=104; 2 pts were retrospectively diagnosed with blast crisis CML). The database lock date was 8/17/16; at this time all pts had completed therapy and 75% had ≥3 yrs of follow-up. Two pts discontinued dasatinib for toxicity (1 allergy and 1 prolonged myelosuppression post HSCT). Nineteen pts met study criteria for HSCT, and 15 received HSCT in CR1 (14.2% of pts). The remaining 91 pts (85.8%) received EsPhALL chemotherapy plus dasatinib without HSCT. Patients tolerated dasatinib combined with chemotherapy well. The primary toxicity was febrile neutropenia and infection: Grade 3+ febrile neutropenia occurred in 75.5% of pts, Grade 3+ sepsis in 18.9%; and Grade 3+ bacteremia in 13.2%. Elevated ALT (21.7%) and AST (10.4%) were the only non-hematologic, non-infectious Grade 3+ adverse events attributed to dasatinib reported in >10% of pts. Relevant Grade 3+ non-hematologic, non-infectious toxicities attributed to dasatinib included pleural effusion (3.8%), edema (3.8%), hemorrhage (2.8%), and cardiac failure (0.8%). No cases of pulmonary hypertension or pulmonary arterial hypertension were reported. All 104 treated Ph+ ALL pts achieved CR. As of the database lock date, 33 events had occurred including 5 deaths (3 in HR3 and 2 in reinduction) due to proven or suspected infection in the 91 patients receiving chemotherapy plus dasatinib, 2 deaths from infection post-HSCT in the 15 HSCT pts, and 26 relapses (chemotherapy 22/86; HSCT 4/12). Sites of relapse included isolated bone marrow (BM; 14), CNS (4), BM+CNS (3), BM+other (2), and other (3). At the time of the interim analysis the 3-yr EFS is 66.0% (95% CI, 54.8-75.0) and the 3-yr OS is 92.3% (95% CI, 85.2-96.1); updated results with all patients having at least 3 years of follow-up will be presented.Conclusions: Addition of dasatinib to the EsPhALL chemotherapy regimen is safe and effective in pediatric Ph+ ALL pts. With only 14% of pts undergoing SCT in CR1, as compared to 80% in the EsPhALL imatinib trial, this trial demonstrates similar outcomes with 3-yr EFS/OS 66.0%/92.3% in this trial vs. published 4-yr EFS/OS 61.9%/72.1% in the EsPhALL imatinib trial. DisclosuresHunger:Novartis: Consultancy; Jazz Pharmaceuticals: Honoraria; Erytech Pharmaceuticals: Consultancy; Amgen: Consultancy, Equity Ownership. Saha:Shire: Research Funding. Gastier Foster:Bristol-Myers Squibb: Research Funding. Cazzaniga:Italian Association for Cancer Research: Research Funding; Fondazione Tettamanti onlus: Employment. Borowitz:Beckman Coulter: Honoraria; Becton-Dickinson Biosciences: Research Funding; HTG Molecular: Honoraria. Gramatges:Bristol Meyer Squibb: Research Funding. Sun:Baxalta: Consultancy. Swanink:Bristol-Myers Squibb: Employment. Schrappe:Baxalta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; JAZZ Pharma: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Medac: Consultancy, Research Funding. Healey:Bristol-Myers Squibb: Employment, Equity Ownership; Pfizer: Equity Ownership.

Oral Mucositis in Pediatric Patients in Treatment for Acute Lymphoblastic Leukemia.

Oral mucositis in oncologic patients is the most undesirable event of the chemotherapeutic treatment. This study aimed to identify damage to the oral cavity resulting from chemotherapy in pediatric patients with acute lymphoblastic leukemia (ALL). This is a prospective study with a sample of 42 children and adolescents evaluated for 10 consecutive weeks after diagnosis. The modified Oral Assessment Guide (OAG) was used, and data were analyzed by Spearman’s rank correlation coefficient (α = 5%). Changes to the normal lips and saliva were positively related to an increase in the OAG score during all 10 weeks of evaluation. Alterations to the labial mucosa were correlated with an increase in the OAG score from the 2nd to 10th week, which was also found for changes in the tongue and in the swallowing function in Weeks 1, 6, 8, 9, and 10 and for gum changes from the 5th to 7th week. No significant vocal changes were correlated with the total OAG score at any point during the monitoring period. Changes in lips, cheek and/or palatal mucosa, labial mucosa, and gum areas and in swallowing function were positively correlated with an increase in the severity of oral mucositis in patients with ALL after beginning chemotherapeutic treatment.

Administration of Dexrazoxane Improves Cardiac Indices in Children and Young Adults With Acute Myeloid Leukemia (AML) While Maintaining Survival Outcomes.

Anthracycline-induced cardiotoxicity remains a significant contributor to late morbidity/mortality in children and young adults with acute myeloid leukemia (AML). The cardioprotectant dexrazoxane can be used as prophylaxis to diminish risk for cardiomyopathy but whether it affects risk of relapse in pediatric AML is unclear. Our institution adopted the use of dexrazoxane before anthracyclines administration for all oncology patients in 2011. We compared patients with AML (ages, 0 to 21 y) who received or did not receive dexrazoxane during the years 2008 to 2013. In total, 44 patients with AML (ages, 4.5 mo to 21.7 y) were included. We identified no statistical difference in 2-year event rate (62% vs. 50%, P=0.41) or 2-year overall survival (69% vs. 69%, P=0.53) between patients receiving (n=28) or not receiving (n=16) dexrazoxane. Ejection fraction (P=0.0262) and shortening fraction (P=0.0381) trended significantly higher in patients that received dexrazoxane compared with those that did not receive dexrazoxane. Utilization of the cardioprotectant dexrazoxane before anthracycline chemotherapy in pediatric patients with AML demonstrated no significant difference in either event rate or overall survival relative to institutional controls and seems to improve cardiac function indices. Further studies in this patient population are needed to confirm these findings.

Abstract A43: Comparative analysis of germline mutations of immune biomarkers pre- and post-HSCT in pediatric cancer patients

Abstract Background/Objectives: Hematopoietic stem cell transplantation (HSCT) is a high risk but curative treatment for many patients with malignant and non-malignant disorders; however, comes with significant and varying chemotherapy-induced toxicities. Here we probe variability in response of DNA collected pre-versus-post autologous-HSCT from pediatric patients. Germline DNA mutations in this population have not been assessed. The overall hypothesis is that new germline mutations are generated by exposure to high-dose chemotherapy in pediatric patients receiving autologous-HSCT and that these genetic changes may also be potential biomarkers of therapeutic response. It has been reported that activation of complement protein, C3, can decrease the risk of infections following HSCT by enabling stem cells to home to the bone marrow and stimulate their differentiation to various immune cells. This process then helps mediate the reconstitution of the immune system via regulatory mechanisms. In this study, chemotherapy-induced germline mutations among pre- and post-autologous HSCT pediatric patients, and the complement component, C3 were evaluated. Developing strategies to identify predictive biomarkers such as variability in chemotherapy-induced mutational burden of C3 among pediatric HSCT patients, could result in innovative approaches to treating these high-risk patients. Design/Methods: Whole exome sequencing from an HSCT biorepository was exploited to assess genetic mutations and search for molecular signatures induced by anti-cancer therapy and autologous HSCT. Peripheral blood mononuclear cells (PBMCs) were isolated pre- and post-HSCT in six pediatric subjects undergoing autologous HSCT following myeloablative conditioning regimen involving carboplatin in combination with other standard of care agents. Whole exome sequencing was performed on germline DNA followed by canonical ingenuity pathway analysis® (IPA). Miliplex MAP Human Complement Panel 2 Multiplex Assay was performed on plasma from each patient pre- and post-HSCT to gain insight into status of the C3 complement protein levels following HSCT. Results: Whole exome DNA sequencing indicated that approximately 10% of genes analyzed (959 genes) were commonly mutated in the germline DNA isolated from the post-HSCT versus the pre-HSCT, which included C3 complement component. Canonical IPA analysis using hypergeometric test indicated that the 10% commonly mutated genes are relevant in at least thirty-six statistically significant biological. Specifically, C3 was found to be associated with the PI3K signaling pathway in immune cells such as B lymphocytes (p=0.04). Preliminary multiplex complement panel data revealed a trend for increased complement protein concentrations for C3 in plasma at day 7 post-HSCT versus plasma collected pre-HSCT. Conclusion: These preliminary experimental findings demonstrate that among the 959 commonly mutated genes, C3 consists of germline DNA mutations, as well as, having differences in expression at the protein level in patients pre- and post-HSCT. While investigation of the other commonly mutated genes and the thirty-five other relevant pathways elucidated in these studies is still ongoing, these studies highlight the importance for further investigation of the complement component C3 and its role in PI3K signaling in immune cells following chemotherapy-induced genetic mutations which may impact patient prognosis and care. Future studies using high-throughput exome sequencing may help elucidate predictive signatures and/or immune biomarkers such as differences in C3 gene and protein for developing personalized treatments for HSCT therapy, for properly managing HSCT-induced toxicities, and ameliorating clinical outcomes. Citation Format: Pankita H. Pandya, Hongyu Gao, ChienWei Chiang, Sydney Ross, Steven Rhodes, Jenny Then, Laura Haneline, Mary Murray, Lang Li, Karen Pollok, Jamie Renbarger. Comparative analysis of germline mutations of immune biomarkers pre- and post-HSCT in pediatric cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A43.

Evaluation of standardized triple intrathecal therapy toxicity in oncohematological pediatric patients.

Background The administration of triple intrathecal therapy with methotrexate, cytarabine and a corticosteroid for the prophylaxis and treatment of neoplastic cellinfiltration in the central nervous system in hematological malignancies is a widespread practice. There is limited information available about its toxicity profile. Several factors related to intrathecal preparation can affect toxicity. Thus, it was decided to standardize intrathecal chemotherapy, trying to obtain the best toxicity profile. Objective To assess the toxicity of a standardized triple intrathecal chemotherapy in oncohematological pediatric patients and to establish risk factors of toxicity. Setting Oncohematological pediatric unit from a tertiary hospital in Spain. Methods Prospective, descriptive and observational study in which all the administrations of standardized triple intrathecal chemotherapy in pediatric patients were registered. Main outcome measure Toxicity of the intrathecal therapy was recorded and possible risk factors were assessed. Results A total of 269 administrations of triple intrathecal chemotherapy were registered in 41 patients (mean age=6.6±3.9years). In 16.7% of the procedures, an adverse event was reported (total number of adverse events=61). 47.5% were grade 1, 47.5% grade 2 and 4.9% grade 3. The administration of intrathecal chemotherapy inpatient and patient age ≥3years were risk factors of toxicity in the multivariate analysis. Conclusions The administration of standardized triple intrathecal chemotherapy is related to a low frequency of toxicity and most of the adverse events registered were mild/moderate. The detection of adverse effects was significantly greater in children with age greater than or equal to three years and in hospitalized patients.

Successful Engraftment of Donor Umbilical Cord Blood (UCB) Cells after Co-Transplantation of Nicord® (Ex Vivo Expanded UCB Progenitor Cells with Nicotinamide) and a Second Unmanipulated Cord Blood Unit after Myeloablative Chemotherapy in Pediatric Patients with Severe Sickle Cell Disease

Background: Patients with severe sickle cell disease (SCD) experience organ damage, poor quality of life, and are at high risk of premature mortality. To date, allogeneic hematopoietic stem cell transplant remains the only available curative therapy for SCD. However, patients with SCD have difficulties finding matched related or unrelated donors for transplantation. UCB could be an alternative graft option for most of the SCD patients but, to date, results with unrelated UCB have not been satisfactory for these hard to engraft patients. NiCord is an ex vivo expanded product manufactured from an entire UCB unit which has been shown to produce rapid and sustained engraftment in combination with a second unmanipulated CB unit or as a standalone graft in adult patients with high-risk hematologic malignancies. We hypothesized that the combination of NiCord with an unmanipulated UCB unit might overcome the engraftment barriers which have limited the success of UCBT in patients with SCD. This strategy is currently evaluated for safety and efficacy in a phase I/II multi-center study in pediatric patients with SCD undergoing myeloablative conditioning therapy. Here we report the results of the first 8 patients in the study.Methods: Patients with SCD and high risk features were eligible if they were between 2 and 45 years of age and if they had adequate performance status and organ function, 2 suitable unrelated UCB units that minimally matched the patient at 4/6 HLA alleles, and if they did not have a fully HLA matched related or unrelated adult donor. The NiCord graft, manufactured by the study sponsor, consisted of a CD133+ expanded cell fraction and an uncultured CD133- T-cell containing fraction. All patients received hydroxyurea beginning on day -35. Patients were subsequently prepared for transplantation with myeloablative chemotherapy: Busulfan/Cyclophosphamide and Anti Thymocyte Globulin (ATG). After the first 3 patients an adverse effect of ATG on the expanded graft was suspected and ATG was replaced by Fludarabine for the subsequent 5 patients. On day 0, the unmanipulated CB unit and NiCord graft were infused. Engraftment, GVHD incidence, treatment related mortality and survival were assessed by conventional parameters.Results: Eight patients, at a median age of 12 years (range 3-16 years) and a median weight of 41 kg (range 17-67 kg) were transplanted. HLA matching between patients and NiCord units was 4/6 (n=7) and 5/6 (n=1); and that between patients and unmanipulated units was 4/6 (n=5) and 5/6 (n=3). Median CD34+ cell dose infused in the NiCord graft was 107 x 105/kg. All 8 transplanted patients initially engrafted neutrophils at a median of 7 days (range 6-20 days) with the NiCord graft. One patient experienced secondary graft failure and died after a second transplant. Ultimately, long term engraftment was derived from NiCord in 2 patients, from the unmanipulated unit in 4 patients and mixed donor chimerism is still sustained in one patient. Patients were hospitalized for initial transplant for a median of 55 days (range 43-100 days). The 7 patients with sustained full donor cell engraftment are currently alive at a median follow-up of 33 months (range 3-45 months), transfusion free and without sickle cell related symptoms. Engraftment and clinical outcomes of the 8 patients are shown in Table 1.Conclusions: NiCord appears to overcome the engraftment barriers of UCB in patients with SCD. Remarkably, sustained donor cell engraftment was obtained in 7/8 patients, despite 4/6 matched UCB units and 5 patients without ATG. NiCord has the potential to increase access to transplantation for patients with SCD by enabling the successful use of unrelated UCB donors. Further optimization of this approach with strategies to further decrease GVHD is warranted. [Display omitted] DisclosuresMartin:Novartis: Other: Support of clinical trials; Jazz Pharmaceuticals: Other: One time discussion panel. Galamidi:Gamida Cell Ltd.: Employment. Peleg:Gamida Cell Ltd.: Employment. Goshen:Gamida Cell Ltd.: Employment. Schwarzbach:Gamida Cell Ltd.: Employment. Snyder:Gamida Cell Ltd.: Employment. Peled:Gamida Cell Ltd.: Employment.

Systemic cisplatin exposure during infancy and adolescence causes impaired cognitive function in adulthood

Cancer survivors diagnosed during infancy and adolescence may be at risk for chemotherapy-related cognitive impairments (CRCI), however the effects of pediatric chemotherapy treatment on adulthood cognitive function are not well understood. Impairments in memory, attention and executive function affect 15–50% of childhood leukemia survivors related to methotrexate exposure. Systemic cisplatin is used to treat a variety of childhood and adult cancers, yet the risk and extent of cognitive impairment due to platinum-based chemotherapy in pediatric patients is unknown. Systemic cisplatin penetrates the CNS, induces hippocampal synaptic damage, and leads to neuronal and neural stem/progenitor cell (NSC) loss. Survivors of non-leukemic cancers may be at risk for significant cognitive impairment related to cisplatin-driven neurotoxicity. We sought to examine the long-term effects of systemic cisplatin administration on cognitive function when administered during infancy and adolescence in a rat model.We performed cognitive testing in adult rats exposed to systemic cisplatin during either infancy or adolescence. Rats treated as adolescents showed significantly poor retrieval of a novel object as compared to controls. Further, cisplatin-treated infants and adolescents showed poor contextual discrimination as compared to controls, and an impaired response to cued fear conditioning. Ultimately, systemic cisplatin exposure resulted in more profound impairments in cognitive function in rats treated during adolescence than in those treated during infancy. Further, exposure to cisplatin during adolescence affected both hippocampus and amygdala dependent cognitive function, suggesting a more global cognitive dysfunction at this age.

Rebound adenoid hyperplasia after chemotherapy in pediatric patients with head and neck lymphoma: MR imaging findings.

To assess MR imaging findings of rebound adenoid hyperplasia after chemotherapy in pediatric patients with head and neck lymphoma. Eight pediatric patients with head and neck lymphoma treated with chemotherapy alone or concurrent chemoradiotherapy were included. All patients underwent pre-therapeutic assessment and post-therapeutic follow-up by MR imaging. The maximum thickness of the adenoid was assessed on transverse T2-weighted images. Rebound adenoid hyperplasia was defined as more than half of the pre-therapeutic thickness after severe atrophy. The pre-therapeutic maximum thickness of the adenoid ranged from 10 to 18mm (mean, 15mm). In all patients, the thickness of the adenoid dramatically decreased (mean 1mm) within 1year after the cessation of chemotherapy. On follow-up MR imaging, rebound adenoid hyperplasia was observed in five patients (63%). Re-atrophy following rebound adenoid hyperplasia was observed in two patients (25%), and no re-atrophy was observed in three patients (37%). Rebound adenoid hyperplasia was not observed in three patients (37%) who were in their late teens, and who had been treated with concurrent chemoradiotherapy. Rebound adenoid hyperplasia was often observed after chemotherapy in pediatric patients with lymphoma. MR imaging was useful for the assessment of rebound adenoid hyperplasia.