Bronchoalveolar lavage (BAL) has been a useful initial diagnostic tool in the evaluation of pulmonary complications after hematopoietic stem cell transplantation (HSCT); however, the diagnostic sensitivity, prevalence, and outcome after BAL versus lung biopsy (LB) in pediatric HSCT patients remains to be determined. We reviewed 193 pediatric HSCT recipients who underwent a total of 235 HSCTs. Sixty-five patients (34%) underwent a total of 101 BALs for fever, respiratory distress, and/or pulmonary infiltrates on chest radiograph and/or computed tomography scan. The 1-year probability of undergoing BAL was 43.0% after allogeneic stem cell transplantation (alloSCT) and 8.5% after autologous stem cell transplantation (autoSCT) (P =.001). Sixteen of the 193 patients (8%) patients underwent 19 LBs. The probability of undergoing LB at 1 year after HSCT was 9.3%. No grade III or IV adverse events related to either procedure were observed. Of the 101 BALs performed, 40% (n = 40) were diagnostic, with a majority revealing a bacterial pathogen. Among the 19 LBs performed, 94% identified an etiology. In multivariate analysis, myeloablative conditioning alloSCT conferred the highest risk of requiring a BAL (hazard ratio [HR],8.5; P = .0002). The probability of 2-year overall survival was 20.2% in patients who underwent BAL, 17.5% for patients who underwent biopsy, and 67.4% for patients who had neither procedure. In multivariate analysis, only the requirement of a BAL was independently associated with an increased risk of mortality (HR, 2.96; P < .0001). In summary, in this cohort of pediatric HSCT recipients, BAL and LB were used in approximately 35% and 8% of pediatric HSCTs with diagnostic yields of approximately 40% and 94%, respectively, and were both associated with poor long-term outcomes.

SummaryCD34-selected haploidentical and unrelated donor allogeneic stem cell transplantation (AlloSCT) in paediatric recipients is associated with sustained engraftment and low risk of acute graft-versus-host disease (aGVHD), but limited by delayed immune reconstitution and increased risk of viral and fungal infection. The optimal dose of donor T cells to prevent graft failure and minimize risk of early opportunistic infection and post-transplant lymphoproliferative disorder (PTLD), while avoiding severe aGVHD, remains unknown. We prospectively studied CD34-selected 8-10/ 10 human leucocyte antigen (HLA)-matched unrelated donor (MUD) peripheral blood stem cell transplantation (PBSCT) in a cohort of 19 paediatric AlloSCT recipients with malignant (n = 13) or non-malignant (n = 6) diseases. T cells were added back to achieve total dose 1·0-2·5 9 10 5 CD3 + /kg. GVHD pharmacoprophylaxis consisted only of tacrolimus. All patients engrafted neutrophils. Probabilities of grade II-IV aGVHD, limited chronic GVHD (cGVHD), and extensive cGVHD were 15·8%, 23·3%, and 0%, respectively. One patient developed PTLD. Oneyear infection-related mortality was 5·6%. T cell immune reconstitution was delayed. One-year overall survival was 82·3%. Five patients with malignant disease ultimately died from progressive disease. CD34-selected MUD PBSCT using a defined dose of T cell add-back resulted in high rates of engraftment and low risk of grade II-IV aGVHD, early transplantationrelated mortality, and extensive cGVHD.

Myeloablative conditioning and allogeneic hematopoietic stem cell transplant (alloHSCT) in children with acute myeloid leukemia (AML) in first complete remission (CR1) may be associated with significant acute toxicity and late effects. Reduced-intensity conditioning (RIC) and alloHSCT in children is safe, feasible, and may be associated with less adverse effects. Gemtuzumab ozogamicin (GO) induces a response in 30% of patients with CD33+ relapsed/refractory AML. The dose of GO is significantly lower when combined with chemotherapy. We examined the feasibility and toxicity of RIC alloHSCT followed by GO targeted immunotherapy in children with CD33+ AML in CR1/CR2. Conditioning consisted of fludarabine 30 mg/m2 × 6 days, busulfan 3.2 to 4 mg/kg × 2 days ± rabbit antithymocyte globulin 2 mg/kg × 4 days followed by alloHSCT from matched related/unrelated donors. GO was administered ≥60 days after alloHSCT in 2 doses (8 weeks apart), following a dose-escalation design (4.5, 6, 7.5, and 9 mg/m2). Fourteen patients with average risk AML received RIC alloHSCT and post-GO consolidation: median age 13.5 years at transplant (range, 1 to 21), male-to-female 8:6, and disease status at alloHSCT 11 CR1 and 3 CR2. Eleven patients received alloHSCT from 5-6/6 HLA-matched family donors: 8 received peripheral blood stem cells, 2 received bone marrow, and 1 received related cord blood transplantation. Three patients received an unrelated allograft (two 4-5/6 and one 9/10) from unrelated cord blood unit and bone marrow, respectively. Neutrophil and platelet engraftment was observed in all assessable patients (100%), achieved at median 15.5 days (range, 7 to 31) and 21 days (range, 10 to 52), respectively. Three patients received GO at dose level 1 (4.5 mg/m2 per dose), 5 at dose level 2 (6 mg/m2 per dose), 3 at dose level 3 (7.5 mg/m2 per dose), and 3 at dose level 4 (9 mg/m2 per dose). Three of 14 patients received only 1 dose of GO after alloHSCT. One patient experienced grade III transaminitis, which resolved; no grade IV transaminitis, no grade III/IV hyperbilirubinemia, or sinusoidal obstructive syndrome were observed. The second dose of GO was given at median of 143 days (range, 120 to 209) after alloHSCT. Probability of grades II to IV acute and chronic graft-versus-host disease were 21% and 33.5%, respectively. Probability of overall survival after RIC alloHSCT and GO consolidation at 1 and 5 years was 78% and 61%, respectively. Probability of 5-year event-free survival after RIC alloHSCT and GO consolidation in patients in CR1 was 78%. No dose-limiting toxicities probably or directly related to GO were observed in this cohort. This preliminary data demonstrate that RIC followed by alloHSCT and consolidation with GO appears to be safe in children and adolescents with CD33+ AML in CR1/CR2. A phase II trial is currently underway investigating this approach with a GO dose of 9 mg/m2 per dose.

Sickle cell disease (SCD) is an autosomal recessive inherited hematological disorder characterized by chronic hemolysis and vaso-occlusion, resulting in multiorgan dysfunction and premature death. The only known curative therapy for patients with severe SCD is myeloablative conditioning and allo-SCT from HLA-matched sibling donors. In this state of the art review, we discuss current and future considerations including patient selection/eligibility, intensity of conditioning regimens, allogeneic graft sources, graft manipulation, mixed donor chimerism, organ function and stability and autologous gene correction stem cell strategies. Recent novel approaches to promote mixed donor chimerism have included the use of matched unrelated adult donors, umbilical cord blood donors, haploidentical familial donors and the utilization of nonmyeloablative, such as reduced intensity and reduced toxicity conditioning regimens. Future strategies will include gene therapy and autologous gene correction stem cell designs. Prospects are bright for novel stem and cellular approaches for patients with severe SCD, and we are currently at the end of the beginning for utilizing cellular therapeutics for the curative treatment of this chronic and debilitating condition.

The literature on the impact of cytomegalovirus (CMV)-related hospitalization in pediatric allogeneic hematopoietic cell transplantation (alloHCT) recipients is limited. The aim of this study was to determine utilization and outcomes of CMV-related hospitalization in alloHCT recipients using a single-center clinical database. This was a retrospective study of 240 children aged 3 months to 21 years (median age, 9.5 years) who underwent alloHCT between 2005 and 2016. The impacts of CMV-related length of stay (LOS) and total healthcare costs were quantified. Factors associated with prolonged CMV viremia (>25 days' duration) were also examined. In at-risk patients with CMV infection, the incidence of CMV viremia was 38% (59 of 155), the median time to onset was 33 days (range, 0 to 292 days), and the median time to resolution was 25 days (range, 3 to 48 days; n = 53). CMV infection was associated with a 23.3-day increase in LOS (P = .004) and added hospital costs of $45,443 (P = .162) compared with patients without CMV infection. In multivariable analysis, receipt of alemtuzumab (P = .027) was associated with CMV viremia of >25 days' duration. Our data show that CMV viremia is associated with prolonged LOS and higher hospital costs and indicate the need for improved and cost-effective CMV prevention strategies. Further studies of patient outcomes and costs in pediatric alloHCT recipients is needed.

Purpose The complexity of results generated from whole-genome sequencing (WGS) and whole-exome sequencing (WES) adds challenges to obtaining informed consent in pediatric oncology. Little is known about knowledge of WGS and WES in this population, and no validated tools exist in pediatric oncology. Methods We developed and psychometrically evaluated a novel WGS and WES knowledge questionnaire, the Precision in Pediatric Sequencing Knowledge Questionnaire (PIPseqKQ), to identify levels of understanding among parents and young adult cancer survivors (≥ 18 years old), off therapy for at least 1 year from a single-institution pediatric oncology outpatient clinic. Participants also completed health literacy and numeracy questionnaires. All participants provided written informed consent. Results One hundred eleven participants were enrolled: 76 were parents, and 35 were young adults. Of the total cohort, 77 (69%) were female, 63 (57%) self-identified as white, and 74 (67%) self-identified as non-Hispanic. Sixty-six (59%) had less than a college degree. Adequate health literacy (n = 87; 80%) and numeracy (n = 89; 80%) were demonstrated. Internal consistency was high (Cronbach’s α = .88), and test-retest reliability was greater than the 0.7 minimum requirement. Scores were highest for genetic concepts related to health and cancer and lowest for WGS and WES concepts. Health literacy and educational attainment were significantly associated with PIPseqKQ scores. Overall, participants felt the benefits of WGS and WES outweighed the potential risks. Conclusion Parents and young adult cancer survivors have some genetics knowledge, but they lack knowledge about WGS and WES. The PIPseqKQ is a reliable tool that can identify deficits in knowledge, identify perceptions of risks and benefits of WGS and WES, and help clinicians tailor their consent discussions to best fit families. The PIPseqKQ also may inform the development of educational tools to better facilitate the informed consent process in pediatric oncology.

The costs associated with allogeneic hematopoietic cell transplantation (alloHCT) are high. Differences in costs and healthcare utilization among potential donor sources for alloHCT are not well characterized in pediatric recipients of alloHCT. One potential reason for these high costs could be the donor source of hematopoietic cells. In this retrospective study, inpatient costs, outpatient costs, and markers of healthcare utilization associated with unrelated donor alloHCT for malignant and non-malignant disease were analyzed for 131 pediatric patients during the first year post-transplant, for whom the donor sources were 38% umbilical cord blood (UCB), 14% unmanipulated peripheral blood stem cell (PBSC), 26% bone marrow (BM), and 22% PBSC with CD-34 selection. The median cost per day survived (through day +365) was lowest for patients receiving PBSC with CD-34 selection $926 (322-5316) as compared to UCB $1918 (491-107,93), unmanipulated PBSC $1516 (630-27,516), and BM $1205 (506-11,181) (p = 0.010). For non-malignant alloHCT, UCB had the highest costs per day survived $1530 (491-793) and PBSC with CD-34 selection had the lowest at $482 (322-3092) (p < 0.001). In a multivariable model for costs per day survived, high-risk disease (p = 0.009) and graft failure (p < 0.001) were significantly associated with higher cost and alloHCT between 2010 and 2015 as compared to 2005 and 2009 (p = 0.017) was significantly associated with lower cost per day survived. This study illustrates important differences in cost and healthcare utilization among the different donor sources used for unrelated alloHCT.

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