Jason L. Freedman

A comparison of immune reconstitution and graft-versus-host disease following myeloablative conditioning versus reduced toxicity conditioning and umbilical cord blood transplantation in paediatric recipients

Immune reconstitution appears to be delayed following myeloablative conditioning (MAC) and umbilical cord blood transplantation (UCBT) in paediatric recipients. Although reduced toxicity conditioning (RTC) versus MAC prior to allogeneic stem cell transplantation is associated with decreased transplant‐related mortality, the effects of RTC versus MAC prior to UCBT on immune reconstitution and risk of graft‐versus‐host disease (GVHD) are unknown. In 88 consecutive paediatric recipients of UCBT, we assessed immune cell recovery and immunoglobulin reconstitution at days +100, 180 and 365 and analysed risk factors associated with acute and chronic GVHD. Immune cell subset recovery, immunoglobulin reconstitution, and the incidence of opportunistic infections did not differ significantly between MAC versus RTC groups. In a Cox model, MAC versus RTC recipients had significantly higher risk of grade II–IV acute GVHD [Hazard Ratio (HR) 6·1, P = 0·002] as did recipients of 4/6 vs. 5–6/6 HLA‐matched UCBT (HR 3·1, P = 0·03), who also had significantly increased risk of chronic GVHD (HR 18·5, P = 0·04). In multivariate analyses, MAC versus RTC was furthermore associated with significantly increased transplant‐related (Odds Ratio 26·8, P = 0·008) and overall mortality (HR = 4·1, P = 0·0001). The use of adoptive cellular immunotherapy to accelerate immune reconstitution and prevent and treat opportunistic infections and malignant relapse following UCBT warrants further investigation.

Potential drug-drug interactions in infant, child, and adolescent patients in children's hospitals.

BACKGROUND AND OBJECTIVES: Hospitalized infants, children, and adolescents are typically exposed to numerous distinct medications during inpatient admissions, increasing their risk of potential drug−drug interactions (PDDIs). We assessed the prevalence and characteristics of PDDI exposure of pediatric patients treated in children’s hospitals. METHODS: This retrospective cohort study included patients <21 years old hospitalized in children’s hospitals throughout the United States. PDDIs were identified by using the MicroMedex DRUG-REAX system. We calculated the patients exposed to PDDIs, stratified according to the seriousness of the interaction; daily and cumulative counts of PDDI exposures; and characterization of the cited potential adverse effects. RESULTS: Of 498 956 hospitalizations in 2011, 49% were associated with ≥1 PDDI, with a “contraindicated” PDDI occurring in 5% of all hospitalizations, a “major” PDDI present in 41%, a “moderate” PDDI in 28%, and a “minor” PDDI in 11%. Opioids were involved in 25% of all PDDIs, followed by antiinfective agents (17%), neurologic agents (15%), gastrointestinal agents (13%), and cardiovascular agents (13%). One-half of all PDDI exposures were due to specific drug pairs occurring in ≤3% of patients per hospital day. The most common potential adverse drug events included additive respiratory depression (in 21% of PDDIs), bleeding risk (5%), QT interval prolongation (4%), reduced iron absorption/availability (4%), central nervous system depression (4%), hyperkalemia (3%), and altered diuretic effectiveness (3%). CONCLUSIONS: Exposure to PDDIs is common among hospitalized children. Empirical data are needed to determine the probability and magnitude of the actual harm for each specific PDDI, particularly for less common drug pairs.

Guideline for the prevention of acute chemotherapy‐induced nausea and vomiting in pediatric cancer patients: A focused update

This update of the 2013 clinical practice guideline provides clinicians with guidance regarding the use of aprepitant and palonosetron for the prevention of acute chemotherapy‐induced nausea and vomiting (CINV) in children. The recommendations were based on three systematic reviews. Substantive changes were made to the guideline recommendations including the inclusion of palonosetron to the 5‐HT3 antagonists recommended for children receiving highly emetogenic chemotherapy (HEC) and the recommendation of aprepitant for children 6 months of age or older receiving HEC. To optimize CINV control in children, future work must focus on closing critical research gaps.

Atypical Chronic Myeloid Leukemia in Two Pediatric Patients.

Atypical chronic myeloid leukemia, BCR‐ABL1‐negative, (aCML) is a rare myeloid neoplasm. Recent adult data suggest the leukemic cells in a subset of patients are dependent on JAK/STAT signaling and harbor CSF3R‐activating mutations. We hypothesized that, similar to adult patients, the presence of CSF3R‐activating mutations would be clinically relevant in pediatric myeloid neoplasms as patients would be sensitive to the JAK inhibitor, ruxolitinib. We report two cases of morphologically similar pediatric aCML, BCR‐ABL1‐negative based on WHO 2008 criteria. One patient had CSF3R‐activating mutation (T618I) and demonstrated a robust response to ruxolitinib, which was used to bridge to a successful stem cell transplant. The other patient did not have a CSF3R‐activating mutation and succumbed to refractory disease <6 months from diagnosis. This report documents CSF3R‐T618I in pediatric aCML and demonstrates the efficacy of ruxolitinib in a pediatric malignancy. As the third documented case successfully treating aCML with ruxolitinib, this case highlights the importance of prompt CSF3R sequencing analysis for myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Pediatr Blood Cancer

Chemotherapy‐Induced Nausea and Vomiting Prophylaxis: Practice Within the Children's Oncology Group

The Childrens Oncology Group (COG) has endorsed a clinical practice guideline (CPG) for acute chemotherapy‐induced nausea and vomiting (CINV) prophylaxis in children with cancer. This project aims to describe current acute CINV prophylaxis practice at COG sites and the gap between this practice and CPG recommendations.

Chemotherapy-Induced Nausea and Vomiting Prophylaxis

The Childrens Oncology Group (COG) has endorsed a clinical practice guideline (CPG) for acute chemotherapy‐induced nausea and vomiting (CINV) prophylaxis in children with cancer. This project aims to describe current acute CINV prophylaxis practice at COG sites and the gap between this practice and CPG recommendations.

Predictors of Antiemetic Alteration in Pediatric Acute Myeloid Leukemia

Better knowledge of patient and cancer treatment factors associated with nausea/vomiting (NV) in pediatric oncology patients could enhance prophylaxis. We aimed to describe such factors in children receiving treatment for acute myeloid leukemia (AML).

A Multicenter Study of Bacterial Blood Stream Infections in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients: The Role of Acute Gastrointestinal Graft-versus-Host Disease

Blood stream infections (BSI) caused by enteric organisms are associated with a particularly high mortality rate in allogeneic hematopoietic cell transplantation (alloHCT) recipients. We conducted a retrospective multicenter study aiming to analyze the risk factors associated with antibiotic resistance and impact of BSI on transplantation-related mortality (TRM) in children after alloHCT. During the study period from 2004 to 2014, 395 children (mean age, 9.4 years) with at least 1 BSI were included. The incidences of resistant gram-negative rods were 20.7% to piperacillin-tazobactam, 10.9% to cefepime, 21% to ceftazidime, 11.4% to levofloxacin, and 8.16% to meropenem. Thirty-eight percent of Enterococcus spp. isolates were resistant to vancomycin. More than 1 episode of BSI was associated with significant increase in the risk of resistance to piperacillin-tazobactam, cefepime, and vancomycin. On multivariate analysis of risk factors for TRM, achievement of neutrophil engraftment by day 30 was associated with lower TRM (P = .002). However, infection with an antibiotic-resistant organism was not associated with TRM. Development of enteric bacterial BSI after the onset of acute gastrointestinal graft-versus-host disease (GVHD) was the strongest predictor of TRM (hazard ratio, 4.786; 95% confidence interval, 2.833 to 8.087; P < .001). In patients with acute gastrointestinal GVHD who subsequently developed enteric bacterial BSI, the incidence of 1-year TRM was 33.4% (SE = 7%), compared with 15.3% (SE = 2%) for those without acute gastrointestinal GVHD (P = .004). Primary prevention of a first episode of BSI is arguably the most important intervention to decrease antibiotic resistance. It is also imperative that we develop strategies to maintain gastrointestinal health, especially in patients with gastrointestinal GVHD, in an effort to prevent subsequent enteric bacterial BSI and improve survival.

Management of Oncologic Emergencies

Abstract Survival in children with cancer has increased dramatically over the past five decades. This progress is due not only to advances in oncologic therapies, but also to advances in supportive care and an improved ability to manage life-threatening complications. Oncologic emergencies can occur as an initial manifestation of cancer, as a side effect of cancer therapy, or at the time of recurrence or progression. The following emergencies are addressed in this chapter: • Metabolic emergencies including hyperleukocytosis, tumor lysis syndrome, and associated electrolyte derangements. • Cardiothoracic emergencies including superior vena cava syndrome and mediastinal masses. • Acute abdominal processes. • Renal dysfunction and hypertension. • Neurologic emergencies. • Endocrinologic emergencies. • Treatment-related emergencies.

Successful treatment of pulmonary mucormycosis in two pediatric hematopoietic stem cell transplant patients

Pulmonary mucormycosis diagnosed immediately after hematopoietic stem cell transplantation frequently portends a poor prognosis. However, here we describe two cases in children that were treated successfully to highlight the efficacy of a multidisciplinary approach. Despite diagnosis in the immediate post‐transplant period and requirement for ongoing immunosuppression to prevent or treat GVHD, both are long‐term survivors due to early surgical debridement with transfusion support and prompt initiation of targeted antifungal therapy. In the absence of evidence‐based treatment guidelines, survival of pulmonary mucormycosis is achievable even in high‐risk patients with a multidisciplinary team to guide management.