Jerelyn Moffet

A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.

Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).

Clinical Outcomes of Children Receiving Intensive Cardiopulmonary Support During Hematopoietic Stem Cell Transplant

Objective: We investigated the short-term and 1-year clinical outcomes of 129 children who received intensive cardiopulmonary support during hematopoietic stem cell transplant. Intensive cardiopulmonary support was defined as receiving at least one of the following interventions: continuous positive pressure ventilation, dopamine infusion greater than or equal to 10 mcg/kg/minute, or the use of any other vasoactive infusion. Duration of intensive cardiopulmonary support, survival to hospital discharge, and predictors of these outcome variables were compared with 387 hematopoietic stem cell transplant patients who did not receive intensive support during the same period. We also report the 1-year survival; presence of chronic graft-versus-host disease; and renal, cardiac, and pulmonary function for all patients. Design: A multicenter retrospective cohort study. Setting: The ICU and hematopoietic stem cell transplant unit of nine pediatric tertiary care centers. Patients: Children undergoing hematopoietic stem cell transplant who required intensive cardiopulmonary support. Interventions: None. Results: Predictors of the need for intensive support included unrelated donor allogeneic transplant, glomerular filtration rate less than 85 mL/minute/1.73 m2, and nonmalignant disease as the indication for transplant. The survival to discontinuation of intensive support for all patients was 62% and 58% for patients who received invasive mechanical ventilatory support. The duration of mechanical ventilation was not predictive of survival. Predictors of intensive support mortality included macroscopic bleeding, engraftment, and pediatric logistic organ dysfunction score greater than one in two domains. Survival to hospital discharge was 50% for the intensive support group and 99% for the nonintensive support group. Overall 1-year survival was 40% in the intensive support population and 65% in the nonintensive support group. There were no significant differences in the survival, rates of chronic graft-versus-host disease, creatinine, forced expiratory volume in 1-minute, cardiac shortening fraction, or performance status in intensive and nonintensive support patients who survived to hospital discharge. Conclusion: Intensive cardiopulmonary support plays an important and potentially life-saving role in the care of pediatric stem cell transplant patients. Survivors of intensive support do not have compromised 1-year survival or organ function compared with children who did not receive intensive support.

Invasive Mechanical Ventilation and Mortality in Pediatric Hematopoietic Stem Cell Transplantation: A Multicenter Study.

Objective: To establish the current respiratory practice patterns in pediatric hematopoietic stem cell transplant patients and investigate their associations with mortality across multiple centers. Design: Retrospective cohort between 2009 and 2014. Setting: Twelve children’s hospitals in the United States. Patients: Two hundred twenty-two pediatric allogeneic hematopoietic stem cell transplant recipients with acute respiratory failure using invasive mechanical ventilation. Interventions: None. Measurements and Main Results: PICU mortality of our cohort was 60.4%. Mortality at 180 days post PICU discharge was 74%. Length of PICU stay prior to initiation of invasive mechanical ventilation was significantly lower in survivors, and the odds of mortality increased for longer length of PICU stay prior to intubation. A total of 91 patients (41%) received noninvasive ventilation at some point during their PICU stay prior to intubation. Noninvasive ventilation use preintubation was associated with increased mortality (odds ratio, 2.1; 95% CI, 1.2–3.6; p = 0.010). Patients ventilated longer than 15 days had higher odds of death (odds ratio, 2.4; 95% CI, 1.3–4.2; p = 0.004). Almost 40% of patients (n = 85) were placed on high-frequency oscillatory ventilation with a mortality of 76.5% (odds ratio, 3.3; 95% CI, 1.7–6.5; p = 0.0004). Of the 20 patients who survived high-frequency oscillatory ventilation, 18 were placed on high-frequency oscillatory ventilation no later than the third day of invasive mechanical ventilation. In this subset of 85 patients, transition to high-frequency oscillatory ventilation within 2 days of the start of invasive mechanical ventilation resulted in a 76% decrease in the odds of death compared with those who transitioned to high-frequency oscillatory ventilation later in the invasive mechanical ventilation course. Conclusions: This study suggests that perhaps earlier more aggressive critical care interventions in the pediatric hematopoietic stem cell transplant patient with respiratory failure requiring invasive mechanical ventilation may offer an opportunity to improve outcomes.

Pediatric Acute Respiratory Distress Syndrome in Pediatric Allogeneic Hematopoietic Stem Cell Transplants: A Multicenter Study

Objective: Immunodeficiency is both a preexisting condition and a risk factor for mortality in pediatric acute respiratory distress syndrome. We describe a series of pediatric allogeneic hematopoietic stem cell transplant patients with pediatric acute respiratory distress syndrome based on the recent Pediatric Acute Lung Injury Consensus Conference guidelines with the objective to better define survival of this population. Design: Secondary analysis of a retrospective database. Setting: Twelve U.S. pediatric centers. Patients: Pediatric allogeneic hematopoietic stem cell transplant recipients requiring mechanical ventilation. Interventions: None. Measurements and Main Results: During the first week of mechanical ventilation, patients were categorized as: no pediatric acute respiratory distress syndrome or mild, moderate, or severe pediatric acute respiratory distress syndrome based on oxygenation index or oxygen saturation index. Univariable logistic regression evaluated the association between pediatric acute respiratory distress syndrome and PICU mortality. A total of 91.5% of the 211 patients met criteria for pediatric acute respiratory distress syndrome using the Pediatric Acute Lung Injury Consensus Conference definition: 61.1% were severe, 27.5% moderate, and 11.4% mild. Overall survival was 39.3%. Survival decreased with worsening pediatric acute respiratory distress syndrome: no pediatric acute respiratory distress syndrome 66.7%, mild 63.6%, odds ratio = 1.1 (95% CI, 0.3–4.2; p = 0.84), moderate 52.8%, odds ratio = 1.8 (95% CI, 0.6–5.5; p = 0.31), and severe 24.6%, odds ratio = 6.1 (95% CI, 2.1–17.8; p < 0.001). Nonsurvivors were more likely to have multiple consecutive days at moderate and severe pediatric acute respiratory distress syndrome (p < 0.001). Moderate and severe patients had longer PICU length of stay (p = 0.01) and longer mechanical ventilation course (p = 0.02) when compared with those with mild or no pediatric acute respiratory distress syndrome. Nonsurvivors had a higher median maximum oxygenation index than survivors at 28.6 (interquartile range, 15.5–49.9) versus 15.0 (interquartile range, 8.4–29.6) (p < 0.0001). Conclusion: In this multicenter cohort, the majority of pediatric allogeneic hematopoietic stem cell transplant patients with respiratory failure met oxygenation criteria for pediatric acute respiratory distress syndrome based on the Pediatric Acute Lung Injury Consensus Conference definition within the first week of invasive mechanical ventilation. Length of invasive mechanical ventilation, length of PICU stay, and mortality increased as the severity of pediatric acute respiratory distress syndrome worsened.

Tolerance and immunity after sequential lung and bone marrow transplantation from an unrelated cadaveric donor.

From the Department of Medicine, New York University School of Medicine, New York, NY. E-mail: Adam.Mor@NYUMC.org. This study was supported by the Hirschl Trust (13-A0-00-000939-01), the New York University Whitehead fellowship (13-A0-00-000897-01), the Colton fellowship, and the American College of Rheumatology Investigator Award (13-A0-00002064-01). Disclose of potential conflict of interest: I. Azoulay-Alfaguter and A. Mor have received research support from the Hirschl Trust, the Colton Fellowship, and the American College of Rheumatology. The rest of the authors declare that they have no relevant conflicts of interest.

High-Frequency Oscillatory Ventilation Use and Severe Pediatric ARDS in the Pediatric Hematopoietic Cell Transplant Recipient

INTRODUCTION: The effectiveness of high-frequency oscillatory ventilation (HFOV) in the pediatric hematopoietic cell transplant patient has not been established. We sought to identify current practice patterns of HFOV, investigate parameters during HFOV and their association with mortality, and compare the use of HFOV to conventional mechanical ventilation in severe pediatric ARDS. METHODS: This is a retrospective analysis of a multi-center database of pediatric and young adult allogeneic hematopoietic cell transplant subjects requiring invasive mechanical ventilation for critical illness from 2009 through 2014. Twelve United States pediatric centers contributed data. Continuous variables were compared using a Wilcoxon rank-sum test or a Kruskal-Wallis analysis. For categorical variables, univariate analysis with logistic regression was performed. RESULTS: The database contains 222 patients, of which 85 subjects were managed with HFOV. Of this HFOV cohort, the overall pediatric ICU survival was 23.5% (n = 20). HFOV survivors were transitioned to HFOV at a lower oxygenation index than nonsurvivors (25.6, interquartile range 21.1–36.8, vs 37.2, interquartile range 26.5–52.2, P = .046). Survivors were transitioned to HFOV earlier in the course of mechanical ventilation, (day 0 vs day 2, P = .002). No subject survived who was transitioned to HFOV after 1 week of invasive mechanical ventilation. We compared subjects with severe pediatric ARDS treated only with conventional mechanical ventilation versus early HFOV (within 2 d of invasive mechanical ventilation) versus late HFOV. There was a trend toward difference in survival (conventional mechanical ventilation 24%, early HFOV 30%, and late HFOV 9%, P = .08). CONCLUSIONS: In this large database of pediatric allogeneic hematopoietic cell transplant subjects who had acute respiratory failure requiring invasive mechanical ventilation for critical illness with severe pediatric ARDS, early use of HFOV was associated with improved survival compared to late implementation of HFOV, and the subjects had outcomes similar to those treated only with conventional mechanical ventilation.

A multicenter investigation of respiratory syncytial viral infection in children with hematopoietic cell transplantation

Hematopoietic cell transplant (HCT) may be a risk factor for morbidity and mortality from respiratory syncytial virus (RSV). Previous studies have been limited by small sample size. We took a multicenter approach with the goal of better understanding the epidemiology, risk factors, treatment, morbidity, and mortality associated with RSV infections among children with HCT in the United States.

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy.Chimeric antigen receptor (CAR) T cell therapies have impressive activity in the treatment of cancer but are associated with potentially fatal toxicities. In light of the approval of CAR T cell therapy for paediatric patients, a panel of experts from the Hematopoietic Stem Cell Transplantation (HSCT) Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network, the CAR T Cell Therapy-Associated Toxicity (CARTOX) Program at The University of Texas MD Anderson Cancer Center, and several other institutions have developed consensus guidelines for the use and management of these treatments in paediatric patients, which are presented herein.

A review of graft versus host disease

Children undergoing hematopoietic stem cell transplant often require intensive care support due to their underlying disease, sepsis, infection, hemorrhage, respiratory failure and organ dysfunction. The majority of children requiring intensive care support have an allogeneic donor. These children carry a higher likelihood of graft versus host disease complicating their medical management. Understanding the process of graft versus host disease is important in the shared care of these children between pediatric intensive care physicians and the bone marrow transplant team.

Allogeneic transplantation for patients with high-risk or refractory neuroblastoma.

9552 Background: While the survival of high-risk neuroblastoma patients has improved with myeloablative chemotherapy (MAC) and 13-cis retinoic acid, 60% of children fail this approach, thus other strategies are needed. As a potential platform for future immunologic-based therapies, we report a retrospective, single-center experience using allogeneic hematopoietic stem cell transplantation (allo-HSCT) following MAC for high risk or recurrent neuroblastoma (NB). METHODS Between June 1994 and November 2007, 17 pediatric patients with high risk or recurrent NB underwent allo-HSCT: allograft sources were related bone marrow (MRD) in 10 patients (pts) and unrelated umbilical cord blood (UCB) in 7 pts. At initial diagnosis the median age was 3.5 years, 16 pts had stage 4 and 1 patient had stage 3 disease. N-myc was amplified in 4 of the 12 pts with available N-myc status. Prior to allo-HSCT, 4 pts were in CR and 7 pts had failed autologous HSCT. Median time from NB diagnosis to allo-HSCT was 14.9 months. Regarding MAC, 7 pts received total body irradiation (TBI)-based regimens: (5 TBI/melphalan (Mel) and 2 TBI/thiotepa), 6 pts received cyclophosphamide (Cy)-based regimens (5 Cy/Mel and 1 Cy-thiotepa), 1 received carboplatin /etoposide/melphalan (CEM), and 3 pts received therapeutic I-131MIBG based regimens (MIBG /CEM in 1, MIBG /campath /Mel in 1, and MIBG/TBI/Mel in 1). RESULTS The median day to neutrophil engraftment (ANC > 500) was 10.5 days for MRD BMT and 22 days for UCBT. The median day to platelet engraftment (plt >20k) for MRD BMT was 29.5 days and for UCBT was 62 days. Acute GVHD (grades I-IV) was seen in 6 patients: 3 grade-I skin, 1 grade-II skin, and 2 grade-III involving both skin and gut. Eleven pts (65%) died at a median of 377 days post-allo-HSCT: 2 infections (PCP pneumonia, Pseudomonal sepsis), 2 MSOF, 1 leukemic relapse (child with recurrent NB and secondary AML) and 6 NB progression. Six patients (5 MRD, 1 UCB) are long-term survivors with overall survival of 35% at 10 years. CONCLUSIONS Allo-HSCT provided durable remission in a very high risk group of NB patients. Therefore a strategy that incorporates early allografting with targeted immunologic therapy should be investigated for refractory or ultra-high risk NB patients.