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1.
Disparities in CMV infection rates by race and ethnicity among pediatric allogeneic hematopoietic cell transplant recipients at a single center
Boge, C. L. K., McDonough, M. H., Newman, A. M., Blumenstock, J., Elgarten, C. W., Freedman, J. L., Olson, T. S., Li, Y., Fisher, B. T.
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Previous literature has reported cytomegalovirus (CMV) infection rate disparities between race and ethnicity groups of hematopoietic cell transplant (HCT) recipients. Because race and ethnicity categorizations are social constructs unlikely to affect biological systems, it is likely there are covariates on the pathway to CMV detection, known as mediators, which would explain the observed disparity. Recent developments in mediation analysis methods enable the analysis of time-to-event outcomes, allowing an investigation of these disparities to also consider the timing of infection detection relative to HCT. OBJECTIVE This study aimed to explore whether racial and ethnic CMV infection disparities existed within a population of HCT recipients at our center and whether clinical covariates explained any observed association. STUDY DESIGN The study includes all allogeneic HCTs performed at the Children's Hospital of Philadelphia January 2004-April 2017 where subjects were CMV polymerase chain reaction (PCR) negative pre-transplant, had known donor/recipient CMV serology, and under blood PCR CMV surveillance. Subjects were followed for 100 days post-HCT. Accelerated failure time models using subject's reported race/ethnicity, dichotomized into non-Hispanic White (NHW) and not NHW, as exposure and time to CMV detection as outcome examined whether selected clinical factors (donor/recipient CMV serostatus, recipient age, transplant indication, hematopoietic cell source, match quality) mediated any identified exposure-outcome association. RESULTS The analysis included 348 HCT episodes from 335 subjects; 86 episodes (24.7%) detected CMV via PCR testing. The accelerated failure time model without mediators estimated non-NHW subjects had fewer CMV-free survival days (Time Ratio: 0.21, 95% Confidence Interval: 0.10-0.44). Any hypothesized mediator mediated at most 5% of the total association between race/ethnicity and time to CMV detection. CONCLUSION Non-NHW HCT recipients had fewer CMV-free survival days than NHW recipients; none of the clinical factors hypothesized to mediate this association accounted for a significant component of total association. Further research should focus on non-clinical factors influenced by systemic racism to better understand its effect on CMV infection among HCT recipients.
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2.
Detection of bronchiolitis obliterans syndrome using nitrogen multiple breath washout in children post-haemopoietic stem cell transplant
Westrupp, N., Berry, C. D., Cole, T., Shanthikumar, S., Welsh, L.
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Bronchiolitis obliterans syndrome (BOS) is a severe complication following haemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI(2.5)) derived from the nitrogen multiple breath washout (N(2)MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. OBJECTIVE We aimed to examine the feasibility of performing surveillance N(2)MBW in children post-HSCT, and in an exploratory analysis, determine if LCI(2.5) led to earlier detection of BOS when compared to spirometric indices. STUDY DESIGN Participants aged 5 - 17 years were recruited prior to receiving HSCT into a prospective, single-centre, feasibility study at the Royal Children's Hospital, Melbourne. N(2)MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9 and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. RESULTS Twenty-one (12 male) children with a mean age of 13.4 (range 9.2-17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI(2.5), while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV(1)). Ninety-nine percent of N(2)MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while two participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI(2.5) ranging from 3 to 5 units and mean reductions in FEV(1) % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI(2.5) values were significantly worse when compared with the no BOS group (p<0.001). Relative changes in LCI(2.5) and FEV(1) were both predictive of BOS at 6 months post HSCT. CONCLUSION This study demonstrates that N(2)MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI(2.5) did not lead to earlier detection of BOS, when compared to spirometry.
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3.
Disease Status and Interval between HCTs Predict Outcome of Pediatric Patients who Undergo a Subsequent HCT for Relapsed Hematologic Malignancy
Epperly, R., Li, Y., Selukar, S., Zeng, E., Madden, R., Mamcarz, E., Naik, S., Qudeimat, A., Sharma, A., Talleur, A., et al
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplant (HCT) have a poor prognosis. While proceeding to subsequent HCT can provide potential for long-term survival, there is limited data to guide which patients are most likely to benefit and which HCT strategies are best in this heavily pre-treated population. OBJECTIVE The goals of this study were to: i) describe the clinical outcomes of a subsequent HCT in pediatric patients with relapsed hematologic malignancies in a cohort enriched for haploidentical donors, and ii) evaluate the association of patient-, disease-, and treatment-related factors with survival. STUDY DESIGN We retrospectively evaluated patients who underwent a subsequent HCT for management of post-HCT relapse at a single institution between 2000-2021. RESULTS Among 106 patients who received a second allogeneic HCT, one-year event-free survival (EFS) was 34% and one-year overall survival (OS) was 46%, with five-year EFS of 26% and five-year OS of 31%. Only disease-related factors were associated with outcome after second HCT, specifically the interval between HCTs and presence or absence of active disease at the time of HCT. In this cohort, patient- and treatment-related factors were not associated with differences in EFS or OS. Patients receiving a third or fourth HCT (n=13) had comparable survival outcomes to those receiving a second HCT. CONCLUSIONS Our experience highlights that a subsequent HCT has curative potential for a subset of patients who relapse after HCT, including those who receive a subsequent HCT from a haploidentical donor. While relapse and treatment-related toxicities remain major challenges, our study indicates that achieving complete remission prior to subsequent HCTs has the potential to further improve outcomes.
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4.
An artificial intelligence-driven predictive model for pediatric allogeneic hematopoietic stem cell transplantation using clinical variables
Echecopar, C., Abad, I., Galán-Gómez, V., Mozo Del Castillo, Y., Sisinni, L., Bueno, D., Ruz, B., Pérez-Martínez, A.
European journal of haematology. 2024
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is a procedure with high morbidity and mortality. Identifying patients for maximum benefit and risk assessment is crucial in the decision-making process. This has led to the development of predictive risk models for HSCT in adults, which have limitations when applied to pediatric population. Our goal was to develop an automatic learning algorithm to predict survival in children with malignant disorders undergoing HSCT. METHODS We studied allogenic HSCTs performed on children with malignant disorders at a third-level hospital between 1991 and 2021. Survival was analyzed using the Kaplan-Meier method, log-rank test for the univariate analysis, and Cox regression for the multivariate analysis. A prognostic index was constructed based on these findings. Lastly, we constructed a predictive model using a random forest algorithm to forecast 1-year survival after HSCT. RESULTS We analyzed 229 HSCTs in 201 patients with a median follow-up of 1.64 years. Variables that impacted on the multivariate analysis were older age (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.12-1.76, p = .003), oldest period of HSCT (HR 0.46, 95% CI 0.29-0.73, p < .001), and mismatched donor (HR 2.65, 95% CI 1.51-4.65, p = .001). Our prognostic index was associated with 3-year overall survival (OS; p < .001). A random forest was developed using as variables: diagnosis, age, year of HSCT, time from diagnosis to HSCT, disease stage, donor type, and conditioning. This achieved 72% accuracy in predicting 1-year OS. CONCLUSIONS Our index and random forest was effective in predicting 1-year survival. However, further validation in diverse populations is necessary to establish their generalizability.
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5.
Surfactant protein D is associated with pulmonary manifestations of chronic graft-versus-host disease following hematopoietic stem cell transplantation
Krarup, A. M., Kielsen, K., Uhlving, H. H., Steffensen, R., Sørum, M. E., Nielsen, K. G., Buchvald, F. F., Sorensen, G. L., Müller, K. G.
Pediatric pulmonology. 2024
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6.
The Impact of NK Cell-Associated Factors on Acute Leukemia Outcomes after Haplo-HSCT with αβ T Cell Depletion in Pediatric Cohort
Glushkova, S., Shelikhova, L., Voronin, K., Pershin, D., Vedmedskaya, V., Muzalevskii, Y., Kazachenok, A., Kurnikova, E., Radygina, S., Ilushina, M., et al
Transplantation and cellular therapy. 2024
Abstract
INTRODUCTION αβ T cell-depletion (αβTCD) is a well-established method of HSCT for children with acute leukemia due to the low rate of graft-versus-host disease and non-relapse mortality. The graft-versus-leukemia effect is generally ascribed to the NK cells, conserved within the graft. However, it is not known whether NK-related factors affect the outcome of αβTCD HSCT. OBJECTIVES The aim of this retrospective study is to explore the impact of NK-alloreactivity (based on donor-recipient KIR mismatch), graft NK-cell dose, and blood NK-cell recovery on day +30 after HSCT on the incidence of leukemia relapse and non-relapse mortality (NRM). STUDY DESIGN The pediatric acute leukemia cohort includes 295 patients first transplanted from haploidentical donors in complete remission. During post hoc analysis, the total cohort was divided into subcohorts by diagnosis (ALL/AML), NK alloreactivity prediction (KIR match/KIR mismatch), graft NK cell dose (less vs. greater than the median value), and blood NK cell recovery on day +30 after HSCT (less vs. greater than the median value). We also investigated the influence of serotherapy (ATG group) versus abatacept + tocilizumab combination (aba+toci group) on relapse risk in the context of KIR mismatch. The relapse and NRM risk were calculated by the cumulative risk method, and groups were compared by Gray's test. Multivariate analysis was provided. RESULTS There was no apparent impact of predicted NK alloreactivity, or other studied NK-related factors for the total cohort. For patients with AML, a significantly higher relapse risk associated with high NK graft content on the background of no predicted KIR mismatch (p=0.002) was shown. Multivariate analysis confirmed this finding (p=0.018); on the other hand, for KIR mismatch cohort, there was a trend towards lower relapse risk associated with high NK-cell dose. The use of ATG was associated with a trend of reduced relapse risk (p=0.074) for AML cohort. There was no significant impact of NK-related factors among ALL patients. CONCLUSIONS Overall, the evaluated NK-related factors did not show a clear and straightforward correlation with the key outcomes of HSCT in the total cohort of children with acute leukemia. In practice, the data support prioritization of KIR-mismatched donors for patients with AML. Importantly, a potential interaction of KIR ligand mismatch and NK cell content in the graft was identified. Indirect evidence suggests that additional cellular constituents of the graft could influence the function of NK cells after HSCT and affect their role as GVL effectors.
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7.
Pre-transplant glomerular hyperfiltration is not a risk factor for increased renal morbidity and mortality in pediatric stem cell transplant patients
Sarkar, N., Myers, K. C., Lane, A., Davies, S. M., Benoit, S. W.
Pediatric blood & cancer. 2024;:e30853
Abstract
Low glomerular filtration rate (GFR) prior to stem cell transplant (SCT) is associated with increased morbidity and mortality. The implications of abnormally high GFRs, or glomerular hyperfiltration, prior to SCT are unknown. Twenty-two of 74 consecutive pediatric SCT patients over 2 years old at a single center were hyperfiltrating prior to SCT, median nuclear medicine GFR 154 mL/min/1.73 m(2) [interquartile range: 146-170]. There was no association between hyperfiltration and any transplant demographics, nor between hyperfiltration and acute kidney injury (p = .8), renal replacement therapy (p = .63), 1-year event-free survival (p = 1), or abnormal creatinine-based estimated GFR at a median follow-up of 4.7 years (p = .73).
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8.
Can extending time between vital sign checks improve sleep in hematopoietic stem cell transplant patients? Testing feasibility, acceptability, and preliminary efficacy
Daniel, L. C., Venella, K. L., Woodard, K., Poliakova, P., Gross, J. Y., Bercovitz, I. N., Moore, D., Barakat, L. P., Freedman, J. L.
Pediatric blood & cancer. 2024;:e30832
Abstract
BACKGROUND Patients undergoing hematopoietic stem cell transplant (HSCT) experience barriers to quality sleep. Frequent vital sign checks are necessary early posttransplant given risk of complications but can disrupt sleep. This study tested feasibility and acceptability of extending time between checking vitals (EVs) from every 4 to every 6 h to improve sleep. PROCEDURE HSCT patients ages 8-21 years (N = 50, mean age = 14.06, SD = 3.58) and their caregivers were enrolled 1-2 days prior to transplant, and 40 patients completed the 15-day study (NCT04106089). Patients wore an actigraph to estimate sleep and provided self- and caregiver-report of sleep. Sleep was observed for nights 0 to +4 posttransplant, and patients were then randomized to EVs either Days +5 to +9 or +10 to +14. Patients were assessed daily for medical eligibility to receive EVs; on days patients were eligible, nightshift nurses (N = 79) reported EV acceptability. RESULTS Of 200 potential nights for EVs (5 nights x 40 patients), patients were eligible for EVs on 126 nights (63% of eligible nights), and patients received EVs on 116 (92%) of eligible nights. Most patients received EVs ≥3 nights (n = 26, 65%, median = 3 nights). Most patients (85%), caregivers (80%), and nurses (84%) reported that patients used the additional 2 h during EVs for sleep, with reporters indicating moderate to high acceptability. There was preliminary evidence of efficacy indicated by caregiver-reported sleep disturbance and actigraphy-estimated improvements in sleep efficiency during EVs. CONCLUSION Extending time between vitals checks is highly acceptable to patients, caregivers, and nurses, and may offer a feasible approach to improve sleep in pediatric HSCT.
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9.
Cytomegalovirus Reactivation as a Risk Factor for All-Cause Mortality in Children Undergoing Hematopoietic Stem Cell Transplantation: Experience Over Two Decades from a Tertiary Referral Center in India
Chakraborty, S., Swaminathan, V. V., Ganesan, K., Duraisamy, S., Meena, S., Jayakumar, I., Krishna, V., Uppuluri, R., Raj, R.
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2024;40(1):91-96
Abstract
The aim of the study was to analyse the burden of cytomegalovirus (CMV) disease in children undergoing hematopoietic stem cell transplantation (HSCT) and its correlation with all-cause mortality. We performed a retrospective study in children up to 18 years of age who underwent allogeneic HSCT between February 2002 to December 2021 in the pediatric blood and marrow transplantation unit. A total of 1035 patients were included where five hundred forty-three (52.4%) patients underwent matched family donor (MFD) HSCT, 213 (20.5%) underwent matched unrelated donor (MUD) HSCT; 279 (26.9%) underwent haploidentical HSCT (T cell replete in 213 and T cell depleted in 66 patients). CMV reactivation was documented in 258 (24.9% patients). CMV was seen in 39 (7.2%) MFD, 77 (36.1%) MUD, 106 T cell replete (49.7%) and 36 T cell depleted (54.5%) transplants. CMV reactivation was predominantly documented in those where donor and recipient were positive (D + /R +) for CMV serostatus (77%)) prior to HSCT. Overall mortality rate was significantly higher in the CMV positive group (103/258, 39.9%), as compared to the CMV negative group (152/777, 19.6%) (p value = 0.0001). CMV was the direct cause of death in 13/1035 children (1.2%). GvHD as a cause of death was found to be significantly higher among those with CMV (n = 32) as compared to those without CMV (n = 14) (35.6 versus 9%, p value = 0.0001). The incidence of CMV reactivation was noted in 25% of HSCT recipients, and predominantly in haploidentical HSCTs. CMV reactivation was shown to significantly impact all-cause mortality and there was a significantly increased risk of mortality due to GvHD among those with CMV reactivation.
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10.
A predictive classifier of poor prognosis in transplanted patients with juvenile myelomonocytic leukemia: a study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire
Meyran, D., Arfeuille, C., Chevret, S., Neven, Q., Caye-Eude, A., Lainey, E., Petit, A., Rialland, F., Michel, G., Plantaz, D., et al
Haematologica. 2024
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Editor's Choice
Abstract
Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myeloproliferative neoplasm requiring hematopoietic stem cell transplantation (HSCT) in most cases. We retrospectively analyzed 119 JMML patients who underwent first allogeneic HSCT between 2002 and 2021. The majority (97%) carried a RAS-pathway mutation, and 62% exhibited karyotypic alterations or additional mutations in SETBP1, ASXL1, JAK3 and/or the RAS pathway. Relapse was the primary cause of death, with a 5-year cumulative incidence of 24.6% (95%CI: 17.1-32.9). Toxic deaths occurred in 12 patients, resulting in treatmentrelated mortality (TRM) of 9.0% (95%CI: 4.6-15.3). The 5-year overall (OS) and event-free survival were 73.6% (95%CI: 65.7-82.4) and 66.4% (95%CI: 58.2-75.8), respectively. Four independent adverse prognostic factors for OS were identified: age at diagnosis >2 years, time from diagnosis to HSCT >6 months, monocyte count at diagnosis >7.2x109/L, and the presence of additional genetic alterations. Based on these factors, we proposed a predictive classifier. Patients with three or more predictors (21% of the cohort) had a 5-year OS of 34.2%, whereas those with none (7%) had a 5-year OS of 100%. Our study demonstrates improved transplant outcomes compared to prior published data, which can be attributed to the synergistic impacts of a low TRM and a reduced yet still substantial relapse incidence. By integrating genetic information with clinical and hematological features, we have devised a predictive classifier. This classifier effectively identifies a subgroup of patients who are at a heightened risk of unfavorable post-transplant outcomes who would benefit novel therapeutic agents and post-transplant strategies.
PICO Summary
Population
Consecutive children diagnosed with Juvenile myelomonocytic leukemia (JMML) in centres in France (n=119)
Intervention
First allogeneic HSCT between 2002 and 2021
Comparison
None
Outcome
The majority (97%) carried a RAS-pathway mutation, and 62% exhibited karyotypic alterations or additional mutations in SETBP1, ASXL1, JAK3 and/or the RAS pathway. Relapse was the primary cause of death, with a 5-year cumulative incidence of 24.6% (95%CI: 17.1-32.9). Toxic deaths occurred in 12 patients, resulting in treatment related mortality (TRM) of 9.0% (95%CI: 4.6-15.3). The 5-year overall (OS) and event-free survival were 73.6% (95%CI: 65.7-82.4) and 66.4% (95%CI: 58.2-75.8), respectively. Four independent adverse prognostic factors for OS were identified: age at diagnosis >2 years, time from diagnosis to HSCT >6 months, monocyte count at diagnosis >7.2x109/L, and the presence of additional genetic alterations. Based on these factors, we proposed a predictive classifier. Patients with three or more predictors (21% of the cohort) had a 5-year OS of 34.2%, whereas those with none (7%) had a 5-year OS of 100%.