Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease.

BACKGROUND: Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. BCL11A is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF. METHODS: We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment. RESULTS: As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period. CONCLUSIONS: This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656).

Global health training opportunities during pediatric hematology/oncology fellowship: Results from a survey of program leaders.

BACKGROUND: There is growing interest in global health (GH) among medical trainees in the United States. However, providing GH training opportunities at the fellowship level presents several challenges. Understanding of barriers and facilitators to implementing GH training is essential for addressing these challenges. METHODS: We developed a comprehensive survey of 65 Likert-scale multiple-choice and open-ended questions to assess perspectives of pediatric hematology/oncology fellowships leaders on GH training. The survey was electronically distributed to program leaders at all ACGME-accredited pediatric hematology/oncology fellowships programs, and data were summarized using descriptive analysis. RESULTS: Of 73 eligible programs, we had a 45.2% response rate with 27 complete and 6 partial responses. Respondents represented programs across the United States, including 19 (57.6%) affiliated with NCI-Designated Cancer Centers. Fourteen programs (43.8%) currently offer GH training opportunities, whereas 18 programs expressed interest in future opportunities (15, 83.3%) or plan to offer them soon (3, 16.7%). Major barriers identified include competing training priorities (23, 82.1%), lack of faculty mentors in the division (23, 82.1%), and lack of dedicated institutional funding (20, 71.4%). Key facilitators include the interest and initiative of current fellows (27, 96.4%), dedicated institutional funding (26, 92.8%), and having established international partnerships (26, 92.8%). CONCLUSIONS: The study reveals strong interest in GH training in pediatric hematology/oncology fellowships. Despite challenges such as competing priorities and a lack of mentors, significant facilitators include current fellows' initiatives, dedicated funding, and established international partnerships. These insights can help shape future initiatives to incorporate GH into pediatric oncology/hematology fellowship training.

A nursing perspective on inpatient sleep and circadian disruptions for pediatric stem cell transplant patients.

BACKGROUND: Children treated with stem cell transplant (SCT) are routinely hospitalized for long periods where they are exposed to significant sleep and circadian disruptions. As nurses play a primary role in symptom management during SCT, we sought to understand their perspective on patient sleep and circadian disruptions, perceived barriers to a good sleep and circadian environment, and suggestions for improvement. PROCEDURE: Four focus groups were conducted with pediatric SCT nurses (N = 25 participants). A semistructured focus group guide was administered, with the discussions recorded and transcribed. A multistage thematic analysis combining prefigured and emergent dimensions was conducted. Our analysis focused on drawing comparisons within and across focus groups to understand the unique work experiences that participants had related to the patient's sleep and circadian environment. RESULTS: Three key themes emerged. First, nurses expressed a high awareness of how disruptive the hospital environment is for patients. Second, nurses described their extensive efforts to try to minimize the impact of these disruptions. Finally, they provided clear recommendations for how to improve upon these concerns, along with barriers that they perceive could impede implementation. CONCLUSIONS: Front-line caregivers on a pediatric SCT unit describe key contributors to sleep/circadian disturbances for patients. Within the constraints of the considerable medical needs of this patient population and the physical room/hospital environment, nurses strive to minimize these disruptions to the best of their ability. It is crucial that hospitals assess and remediate these disturbances for these children that have important implications for overall health.

Impact of cytoreduction and remission status on hematopoietic cell transplantation outcomes in pediatric myelodysplastic syndrome and related disorders.

BACKGROUND: The role of cytoreduction prior to hematopoietic cell transplant (HCT) for patients with pediatric myelodysplastic syndrome (MDS) and related disorders remains unclear. PROCEDURE: We performed a single-center retrospective analysis of pre-transplant disease management and subsequent HCT outcome for pediatric patients with MDS and related disorders who underwent HCT between 2010 and 2020. RESULTS: Total 62 patients (median age 11 years) with idiopathic MDS (n = 16), MDS secondary to an underlying germline condition (n = 11), secondary acute myeloid leukemia (n = 9), myeloproliferative neoplasms (n = 8), and treatment-related myeloid neoplasms (n = 18) received an allogeneic HCT. Cytoreduction prior to HCT was performed in 30/62 (48%) patients; this subset of patients had higher risk disease characteristics, including a higher blast count on presentation. In the overall cohort, use of cytoreduction before HCT was associated with higher rates of relapse (cumulative incidence of relapse 24 months post HCT: 48.1% [27.5%-66.1%]) for those who received cytoreduction versus 16.6% (5.9%-32.1%) for those who did not (p = .03). There was a trend toward decreased overall survival (OS) for those patients who received cytoreduction (24 months post HCT 57.1% vs. 75.3%, respectively; p = .06). OS for patients who received cytoreduction and attained measurable residual disease (MRD) negativity prior to HCT was superior compared to those with persistent disease (24 months post HCT 63.9% [36%-81.2%] vs. 33.3% [7.8%-62.3%], respectively; p = .04). CONCLUSION: Cytoreduction did not provide survival benefit in our overall cohort, but its increased use in children with higher risk disease impacted the analysis. Patients receiving cytoreduction and achieving MRD-negative status before HCT demonstrated improved OS compared to those with persistent disease.

Comparison of toxicity following single versus tandem autologous transplant regimens for pediatric medulloblastoma.

BACKGROUND: Medulloblastoma outcomes have improved with craniospinal irradiation and chemotherapy, but such therapy has resulted in poor neurocognitive outcomes for young patients. Chemotherapy-only regimens with autologous transplant have been implemented with the intention of avoiding radiation. It is not yet known whether single or tandem transplantation is superior with respect to efficacy and/or safety. METHODS: We performed a retrospective review of children with medulloblastoma treated at Dana-Farber Cancer Institute from 1996 to 2016 who received either single or tandem autologous transplantation after completion of induction chemotherapy. We compared safety and outcome data between the two groups. RESULTS: Among 23 patients, 12 received tandem transplants. Median follow-up was 6.4 years (IQR = 0.8-10.5). There was no statistically significant difference in 5-year EFS or OS between the single (70.7 ± 14%, 80.2 ± 13%) and tandem transplant groups (57.1 ± 15%, 79.6 ± 13%). Seven tandem transplant patients received subsequent radiation while only four required radiation in the single transplant group (p = .41). In the single transplant regimen, patients experienced longer antibiotic duration (p = .03) and LOS (p = .01) and a trend toward increased number of transfusions (p = .06). Four cases of veno-occlusive disease were reported in the single transplant group (p = .04). CONCLUSIONS: Outcomes were similar between regimens, but the single transplant regimen had more hepatic complications. These data suggest that tandem transplant regimens may have reduced toxicity compared to the single transplant regimen with similar outcome measures.

A study assessing the feasibility of randomization of pediatric and young adult patients between matched unrelated donor bone marrow transplantation and immune-suppressive therapy for newly diagnosed severe aplastic anemia: A joint pilot trial of the North American Pediatric Aplastic Anemia Consortium and the Pediatric Transplantation and Cellular Therapy Consortium.

BACKGROUND: Recent data show survival after matched unrelated donor (MUD) bone marrow transplantation (BMT) is similar to matched sibling procedures for young patients with severe aplastic anemia (SAA). Donor delays, risk of transplant-related mortality (TRM), and concern about chronic graft versus host disease raise questions about whether MUD BMT or immune suppression therapy (IST) should be preferred initial therapy for young patients lacking matched sibling donors. PROCEDURE: We performed a pilot trial to assess the feasibility of randomizing patients under age 26 with newly diagnosed SAA to receive IST versus MUD BMT. Primary aims assessed the acceptability of randomization and timing of BMT. Secondary aims measured toxicities, response, and survival. RESULTS: Sixty-seven patients with possible SAA were screened at nine centers. Of 57 with confirmed SAA, 23 underwent randomization and received therapy with a median follow-up of 18 months. Of 12 randomized to BMT, 10 started BMT as initial therapy at a median of 36 days after randomization. One BMT recipient experienced secondary graft failure, requiring a second procedure. Six of 11 randomized to IST responded, whereas five with refractory disease underwent successful salvage BMT. One patient achieving complete response relapsed after discontinuation of immune suppression and died of infection after salvage BMT. CONCLUSIONS: This feasibility study showed that a high percentage of patients underwent randomization and received up-front MUD BMT. Our study lays the groundwork for a larger randomized trial that will define best initial therapy for young patients with SAA who have an available MUD.

Incidence, risk factors, and outcome of blood stream infections during the first 100 days post-pediatric allogeneic and autologous hematopoietic stem cell transplantations.

Bloodstream infections (BSI) are a frequently observed complication after hematopoietic stem cell transplant (HSCT). Retrospective analysis of clinical and microbiological data during the first 100 days from 302 consecutive pediatric patients who underwent HSCT for a malignant disease at our institute between January 2013 and June 2017. A total of 164 patients underwent autologous and 138 allogeneic HSCT. The overall incidence of BSI was 37% with 92% of infectious episodes occurring during the pre-engraftment phase. Gram-positive bacteria (GPB) accounted for 54.6% of the isolated pathogens, gram-negative bacteria (GNB) for 43.9%, and fungi for 1.4%. Coagulase-negative staphylococci and Escherichia coli were the most commonly isolated GPB and GNB, respectively. Forty-five percent of GNB were extended-spectrum beta-lactamase producers and 21% were multidrug-resistant organisms. Fluoroquinolone resistance was 92% and 68%, among GPB and GNB, respectively. Risk factors for BSI in univariate analysis were allogeneic HSCT, delayed time to engraftment more than 12 days, previous BSI before HSCT, and alternative donor. In multivariate analysis, only HSCT type (allogeneic vs autologous P = .03) and previous BSI within 6 months before HSCT (P = .016) were significant. Overall survival at day 100 was 98% and did not differ significantly between patients with and without BSI (P = .76). BSI is common in children undergoing HSCT for malignant diseases. Allogeneic HSCT recipients and previous BSI within 6 months before HSCT are associated with increased risk of post-transplant BSI. With current supportive measures, BSI does not seem to confer an increased risk for 100-day mortality.

Therapeutic Impact and Complications Associated with Surgical Lung Biopsy after Allogeneic Hematopoietic Stem Cell Transplantation in Children.

Hematopoietic stem cell transplantation (HSCT) in the pediatric population is associated with pulmonary complications in 25% of recipients. The role of surgical lung biopsy (SLB) remains unclear because of concerns about both the therapeutic impact and morbidity associated with the procedure. A retrospective review of consecutive allogeneic HSCT recipients at Dana-Farber and Boston Children's Hospital Cancer and Blood Disorders Center between 2006 and 2016 was performed. All recipients who underwent SLB during the study period were identified and charts reviewed for perioperative complications, histopathologic findings, and changes in therapy delivered. Pearson's chi-square test and Student's t-test (or appropriate nonparametric test) were used to evaluate the associations between perioperative complication and categorical and continuous variables, respectively. Five hundred fifty-five HSCTs were included, among which 48 SLBs (8.6%) were identified. Median follow-up time was 24 months (range, 0 to 139). Thirty-day postoperative morbidity was 16.7% and 30-day postoperative mortality 10.4% (n = 5). The overall 30-day postoperative complication rate (including mortality) was 20.8% (n = 10). No mortalities were directly attributable to SLB. Definitive diagnoses were identified in 70.8% of SLBs (n = 34), and therapeutic changes occurred in 79.2% (n = 38). Overall, 83.3% of SLBs (n = 40) either provided a diagnosis or led to a change in therapy. SLB has an acceptable risk of perioperative complications in this medically complicated and often severely ill population. In most HSCT patients, SLB aids in defining the etiology of pulmonary infiltrates and can inform therapeutic decisions in patients where noninvasive diagnostic modalities have failed to provide a definitive diagnosis.

A single institutional review of pediatric Bacillus spp. bloodstream infections demonstrates increased incidence among children with cancer.

BACKGROUND: Bacillus species are known to cause severe infection in immunocompromised hosts. The incidence of Bacillus bloodstream infections and characteristics of infection among children with cancer or indication for hematopoietic cell transplant (HCT) is unknown. METHODS: We performed a retrospective medical record review of all cases of Bacillus bacteremia between January 1, 2005, and December 31, 2014, at Boston Children's Hospital. We report average incidences from 2012 to 2014. We performed a detailed review of infections among children with cancer or undergoing HCT and a case-control study to evaluate whether neutropenia at diagnosis caries higher risk of Bacillus infection for children with acute lymphoblastic leukemia (ALL). RESULTS: One hundred fourteen children developed Bacillus bacteremia during the study period, with an estimated incidence of 0.27/1,000 patients. Among children treated for cancer or undergoing HCT, there were 37 bloodstream infections (2.0/1,000 patients). Of the 37 oncology/HCT patients, oncologic diagnoses included ALL (18), acute myeloid leukemia (3), myelodysplastic syndrome (1), solid tumors (8), and 7 children were undergoing HCT. The incidence of infection among children with ALL was 34/1,000 patients and all central nervous system (CNS) infections (6) and deaths (3) occurred in this population. Neutropenia at time of diagnosis in children with ALL was not associated with risk of infection (P = 0.17). DISCUSSION: We report the first hospital-wide analysis of Bacillus infection and found that immunocompromised children experience a significant proportion of Bacillus infections. Children with ALL have a high incidence of infection and are at higher risk of CNS involvement and death.

Sun exposure and protection practices in children after allogeneic hematopoietic stem cell transplantation: A Survey-Based Cross-Sectional Cohort Study.

BACKGROUND/OBJECTIVE: Pediatric hematopoietic stem cell transplantation (HSCT) patients are at an increased risk for skin cancers. Sun exposure is a significant modifiable environmental risk factor. While patient education on sun protection and avoidance behaviors with regular dermatology evaluations are crucial for pediatric HSCT patients, the real-life practice of these sun-protection recommendations in this patient population compared to their peers is unknown. METHODS: A survey-based cross-sectional cohort study was performed in pediatric HSCT patients seen at the Dana-Farber Cancer Institute and Boston Children's Hospital over a 1.5-year period compared with age/sex/Fitzpatrick skin phototype-matched healthy controls. Study participants were surveyed using the validated Glanz survey for pediatric sun protection behavioral research. RESULTS: Eighty-five pediatric HSCT patients and 85 controls completed the study. Pediatric HSCT patients more frequently used sunscreen, hats, umbrellas, and sunglasses and obtained full-body skin exams compared to controls. No difference was observed in sun exposure during hours of peak sun intensity, frequency of purposeful tanning, tanning bed use, and the number of painful sunburns received between pediatric HSCT patients and controls. CONCLUSIONS: Although pediatric HSCT patients practice more sun protection behaviors, they experienced harmful sunburns and intentional tanning behaviors at the same rate as their peers. Patient-directed counseling and strategies to improve patient adherence to optimal sun protection behaviors could have a significant impact on the dermatology quality of life in pediatric HSCT patients.

Pretransplant functional imaging and outcome in pediatric patients with relapsed/refractory Hodgkin lymphoma undergoing autologous transplantation.

BACKGROUND: Pretransplant functional imaging (FI), particularly a negative positron emission tomography (PET), is a strong predictor of outcome in adults with relapsed or refractory Hodgkin lymphoma (HL), but data in pediatrics are limited. METHODS: The medical records of 49 consecutive pediatric patients, who received autologous transplant at a single institution, were retrospectively analyzed. All patients had either gallium or PET scan before transplant and were conditioned with carmustine, etoposide, cytarabine, and melphalan (BEAM). Deauville scores were retrospectively assigned for patients with PET (score ≥ 4 positive). RESULTS: Of the 49 patients (median age, 16.2 years), 41 (84%) were pretransplant FI negative and eight (16%) were pretransplant FI positive, after first- to fourth-line salvage therapy, and a median of two salvage cycles. Eighteen patients (37%) received posttransplant radiation. At a median follow up of 46 months, 45 patients (92%) were alive and disease free, and there were three nonrelapse deaths and only one relapse death (Deauville score of 5). The 4-year progression-free survival (PFS) for the entire cohort was 92% (95% confidence interval [CI]: 78-97), and PFS based on pretransplant disease status was 95% (95% CI: 82-99%) in the negative FI group versus 75% (95% CI: 31-93) if positive FI (P = 0.057). CONCLUSION: Our analysis revealed outstanding outcomes for children and adolescents with relapsed/refractory HL. There were too few relapses to identify the predictive value of pretransplant metabolic status, but pediatric patients with relapsed/refractory HL and a negative pretransplant FI had excellent survival.

Nonmalignant late cutaneous changes after allogeneic hematopoietic stem cell transplant in children.

BACKGROUND: There are limited pediatric data on nonmalignant cutaneous changes, including autoimmune conditions and permanent alopecia, after hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We sought to characterize late cutaneous changes and associated risk factors after allogeneic HSCT in children. METHODS: A cross-sectional cohort study of pediatric HSCT recipients was performed at a single institution. All participants underwent a full skin examination. RESULTS: The median visit age was 13.8 years, with a median time post-HSCT of 3.6 years. Of 85 patients, 14% (n = 12) had vitiligo, 16% (n = 14) had psoriasis/sebopsoriasis, 25% (n = 21) had alopecia, and 6% (n = 5) had nail changes. Factors significantly associated with vitiligo included a history of chronic graft-versus-host disease (cGVHD), transplant indication of primary immunodeficiency, and younger age at transplant (<10 years of age). Fifty-two percent of patients with alopecia had androgenetic alopecia patterns. Factors significantly associated with alopecia included cGVHD, busulfan conditioning, and family history of early male pattern alopecia. All patients with nail changes had cGVHD. LIMITATIONS: The cross-sectional design did not allow time of onset identification. Histopathologic correlation was not performed. CONCLUSION: Pediatric HSCT recipients, particularly those with cGVHD, are at risk for developing nonmalignant late cutaneous changes.

Recommendations on RBC Transfusion Support in Children With Hematologic and Oncologic Diagnoses From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative.

OBJECTIVES: To present the recommendations and supporting evidence for RBC transfusions in critically ill children with hematologic and oncologic disease from the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. DESIGN: Consensus conference series of international, multidisciplinary experts in RBC transfusion management of critically ill children. METHODS: The panel of 38 experts developed evidence-based and, when evidence was lacking, expert-based clinical recommendations and research priorities for RBC transfusions in critically ill children. The hematologic/oncologic subgroup included seven experts. Electronic searches were conducted using PubMed, EMBASE, and Cochrane Library databases from 1980 to May 2017. Agreement was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. RESULTS: The hematologic/oncologic subgroup developed 14 recommendations (seven clinical, seven research); all achieved greater than 80% agreement. In patients with sickle cell disease, Transfusion and Anemia Expertise Initiative recommends: 1) RBC transfusion to achieve a target hemoglobin concentration of 10 g/dL rather than hemoglobin of less than 30% prior to surgical procedures requiring general anesthesia and 2) exchange transfusion over simple (nonexchange) transfusion if the child's condition is deteriorating (based on clinical judgment), otherwise a simple, nonexchange RBC transfusion is recommended. There is insufficient evidence to make recommendations on transfusion thresholds for patients with sickle cell disease prior to minor procedures, with acute stroke or with pulmonary hypertension. For patients with oncologic disease or undergoing hematopoietic stem cell transplant, a hemoglobin concentration of 7-8 g/dL is recommended. Due to lack of evidence, research is needed to clarify the appropriate transfusion thresholds in these patients. CONCLUSIONS: Transfusion and Anemia Expertise Initiative developed specific pediatric recommendations regarding RBC transfusion management in critically ill children with sickle cell disease, oncologic disease, and hematopoietic stem cell transplant and recommendations to help guide future research priorities.

Consensus Recommendations for RBC Transfusion Practice in Critically Ill Children From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative.

OBJECTIVES: To date, there are no published guidelines to direct RBC transfusion decision-making specifically for critically ill children. We present the recommendations from the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. DESIGN: Consensus conference series of multidisciplinary, international experts in RBC transfusion management of critically ill children. SETTING: Not applicable. INTERVENTION: None. SUBJECTS: Children with, or children at risk for, critical illness who receive or are at risk for receiving a RBC transfusion. METHODS: A panel of 38 content and four methodology experts met over the course of 2 years to develop evidence-based, and when evidence lacking, expert consensus-based recommendations regarding decision-making for RBC transfusion management and research priorities for transfusion in critically ill children. The experts focused on nine specific populations of critically ill children: general, respiratory failure, nonhemorrhagic shock, nonlife-threatening bleeding or hemorrhagic shock, acute brain injury, acquired/congenital heart disease, sickle cell/oncology/transplant, extracorporeal membrane oxygenation/ventricular assist/ renal replacement support, and alternative processing. Data to formulate evidence-based and expert consensus recommendations were selected based on searches of PubMed, EMBASE, and Cochrane Library from 1980 to May 2017. Agreement was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. MEASUREMENTS AND RESULTS: The Transfusion and Anemia Expertise Initiative consensus conference developed and reached consensus on a total of 102 recommendations (57 clinical [20 evidence based, 37 expert consensus], 45 research recommendations). All final recommendations met agreement, defined a priori as greater than 80%. A decision tree to aid clinicians was created based on the clinical recommendations. CONCLUSIONS: The Transfusion and Anemia Expertise Initiative recommendations provide important clinical guidance and applicable tools to avoid unnecessary RBC transfusions. Research recommendations identify areas of focus for future investigation to improve outcomes and safety for RBC transfusion.

A modified γ-retrovirus vector for X-linked severe combined immunodeficiency.

BACKGROUND: In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. METHODS: We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). RESULTS: All patients received bone marrow-derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients. CONCLUSIONS: This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.).

Hematopoietic stem cell transplantation outcomes for 11 patients with dedicator of cytokinesis 8 deficiency.

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Reports of outcomes are still limited. OBJECTIVE: We sought to analyze the results of HSCT in patients with DOCK8 deficiency and report whether approaches resulting in mixed chimerism result in clinically relevant immune reconstitution. METHODS: We performed a retrospective chart review of 11 patients with DOCK8 deficiency and measured DOCK8 expression and cytokine production. RESULTS: Of 11 patients, 7 received HSCT from related and 4 from unrelated donors; 9 patients received busulfan-based conditioning regimens. Survival was excellent (10 [91%] of 11 patients alive), including a patient who had undergone liver transplantation. Patients showed significant improvements in the frequency and severity of infections. Although eczema resolved in all, food allergies and high IgE levels persisted in some patients. Lymphopenia, eosinophilia, low numbers of naive CD8(+) T cells and switched memory B cells, and TH1/TH2 cytokine imbalance improved in most patients. Although the 8 matched related or unrelated donor recipients had full donor chimerism, all 3 recipients of mismatched unrelated donor HSCT had high levels of donor T-cell chimerism and low B-cell and myeloid cell chimerism (0% to 46%). Almost all switched memory B cells were of donor origin. All patients, including those with mixed chimerism, mounted robust antibody responses to vaccination. CONCLUSION: Allogeneic HSCT ameliorated the infectious and atopic symptoms of patients with DOCK8 deficiency. In patients with mixed chimerism, selective advantage for donor-derived T cells and switched memory B cells promoted restoration of cellular and humoral immunity and protection against opportunistic infection.

Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens.

The safety and efficacy of reduced-intensity conditioning (RIC) regimens for the treatment of pediatric acute myeloid leukemia is unknown. We compared the outcome of allogeneic hematopoietic cell transplantation in children with acute myeloid leukemia using RIC regimens with those receiving myeloablative-conditioning (MAC) regimens. A total of 180 patients were evaluated (39 with RIC and 141 with MAC regimens). Results of univariate and multivariate analysis showed no significant differences in the rates of acute and chronic graft-versus-host disease, leukemia-free, and overall survival between treatment groups. The 5-year probabilities of overall survival with RIC and MAC regimens were 45% and 48%, respectively (P = .99). Moreover, relapse rates were not higher with RIC compared with MAC regimens (39% vs 39%; P = .95), and recipients of MAC regimens were not at higher risk for transplant-related mortality compared with recipients of RIC regimens (16% vs 16%; P = .73). After carefully controlled analyses, we found that in this relatively modest study population, the data supported a role for RIC regimens for acute myeloid leukemia in children undergoing allogeneic hematopoietic cell transplantation. The data also provided justification for designing a carefully controlled randomized clinical trial that examines the efficacy of regimen intensity in this population.

Safety of peritoneal and pleural drain placement in pediatric stem cell transplant recipients with severe veno-occlusive disease.

Hepatic VOD (veno-occlusive disease) is a serious complication of HSCT (hematopoietic stem cell transplantation) and has historically been associated with high mortality. This obstruction to hepatic flow often results in fluid collections in the peritoneal and pleural cavities. Catheter placement to drain ascites or pleural fluid may reduce intra-abdominal hypertension and/or improve respiratory parameters. The safety of these interventions among critically ill, immunocompromised children is unknown. Among 32 HSCT recipients (2000-2012) with severe VOD, we assessed the primary outcome of procedural complication from peritoneal drain placement. Twenty-four (75%) patients underwent peritoneal drain placement. No patient sustained visceral perforation or hemorrhage with drain placement. Overall mortality was 47% (n = 15). The procedure was not associated with increased overall mortality (p > 0.99). Eight (25%) peritoneal drains required replacement for malfunction. Of 24 patients with peritoneal drains, one (4%) patient had a positive culture from ascitic fluid. Eight (25%) patients underwent pleural drain placement. No pleural drain-related procedural complication or infection occurred. Four (50%) of the eight patients with pleural drains had de-escalation in oxygen requirement at drain removal, compared to time of placement. In this study, peritoneal and pleural drains were safe interventions for children with severe VOD.

Outcomes Following Bone Marrow Transplantation in Children With Accelerated Phase or Blast Crisis Chronic Myelogenous Leukemia in the Era of Tyrosine Kinase Inhibitors.

The management of chronic myelogenous leukemia (CML) in children changed dramatically with the introduction of tyrosine kinase inhibitors (TKIs). Unfortunately, outcomes for patients presenting in an advanced stage-accelerated phase or blast crisis CML-continues to be poor, requiring chemotherapy and allogeneic hematopoietic stem cell transplant (HSCT) to attempt cure. Integration of TKIs in the therapy of advanced CML is still an area of active investigation. There are little published data on TKI use in children with advanced stage CML. We performed a retrospective review of all children treated at our institution between January 1, 2010 and June 30, 2013, and identified 5 children, age 12 to 18 years, with advanced stage CML. All patients were treated with a TKI before HSCT and TKIs were restarted post-HSCT in 4/5 with a goal of continuing until 2 years posttransplant. At time of HSCT all were in a morphologic and cytogenetic remission; 1 patient had also achieved molecular remission. All patients are alive and in molecular remission at an average of 38 months (range, 14 to 51 mo) following transplant. Our experience indicates that TKIs are safe and well tolerated in children both pretransplant and posttransplant and may improve outcomes in this aggressive disease.

Incidence and causes of hospital readmission in pediatric patients after hematopoietic cell transplantation.

Allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) provide the potential to cure otherwise fatal diseases but they are resource-intense therapies. There is scant literature describing the burden of hospital readmission in the critical 6-month period of immunosuppression after HCT. We report the incidence, causes, and outcomes of readmission in the 6 months after day 0 of HCT and in the 30 days after hospital discharge. This study is an institutional review board-approved retrospective medical record review of children who underwent HCT at a single institution. Between January 1, 2008 and December 31, 2011, 291 children underwent HCT at our institute. Of these, 140 patients were excluded because they were not followed primarily at our institute for the first 6 months after transplantation, 14 patients were excluded because they died during their initial hospitalization, and 1 patient was excluded because the initial hospitalization was longer than 6 months. Of the remaining 136 patients, 63% had at least 1 readmission. Of the patients who underwent allo-HCT, 78% were readmitted, in contrast to 38% of auto-HCT patients (P < .001). For the 206 readmissions, the mean length of hospital stay was 10.7 days (range, 1 to 129). Seventy-two percent of auto-HCT patients were initially readmitted for fever, and 46% ultimately had a source identified. No risk factors for readmission were found in the auto-HCT group. Fifty-two percent of allo-HCT patients were readmitted for fever and 28% of these patients ultimately had an identified source. Gastrointestinal-related problems accounted for 30% of primary readmissions among allo-HCT patients. Patients with an unrelated donor had a trend towards increased rates of 30-day readmission (P = .06) and were more likely to have a second readmission (P = .002). Patients who were cytomegalovirus (CMV) positive before transplantation were more likely to be readmitted (P = .02). The majority of children who undergo HCT are readmitted during the critical 180 days after transplantation. Readmission is much more common among allo-HCT patients, in particular those with unrelated donors and CMV-positive serologies before transplantation. Fever is the most common cause of readmission in these patients, and serious infections are identified in a significant portion of patients. These findings and future research in this area will help improve both patient education and resource utilization.