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Intensive Care Risk and Long-Term Outcomes in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients
Zinter, M. S., Brazauskas, R., Strom, J., Chen, S., Bo-Subait, S., Sharma, A., Beitinjaneh, A., Dimitrova, D., Guilcher, G., Preussler, J. M., et al
Blood advances. 2023
Abstract
Allogeneic hematopoietic cell transplantation (HCT) can be complicated by life-threatening organ toxicity and infection necessitating intensive care. Epidemiologic data have been limited by single-center studies, poor database granularity, and a lack of long-term survivors. To identify contemporary trends in ICU utilization and long-term outcomes, we merged data from the Center for International Blood and Marrow Transplant Research and the Virtual Pediatric Systems databases. We identified 6,995 pediatric HCT patients age ≤21 years who underwent 1st allogeneic HCT between 2008-2014 across 69 centers in the United States or Canada and followed patients until the year 2020. ICU admission was required for 1067 patients (8.3% by day +100, 12.8% by 1 year, and 15.3% by 5 years post-HCT), and was linked to demographic background, pre-transplant organ toxicity, allograft type and HLA-match, and the development of graft-versus-host disease or malignancy relapse. Survival to ICU discharge was 85.7% but more than half of ICU survivors required ICU readmission, leading to 52.5% and 42.6% survival at 1- and 5-years post-ICU transfer, respectively. ICU survival was worse among patients with malignant disease, poor pre-transplant organ function, and alloreactivity risk-factors. Among 1-year HCT survivors, those who required ICU in the first year had 10% lower survival at 5 years and developed new dialysis-dependent renal failure at a greater rate (p<0.001). Thus, while ICU management is common and survival to ICU discharge is high, ongoing complications necessitate recurrent ICU admission and lead to a poor 1-year outcome in select high-risk patients.
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Adapting the HCT-CI Definitions for Children, Adolescents, and Young Adults with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Cell Transplantation
Friend, B., Broglie, L., Logan, B. R., Chhabra, S., Bupp, C., Schiller, G., Beitinjaneh, A., Perez, M. A. D., Guilcher, G. M. T., Hashem, H., et al
Transplantation and cellular therapy. 2022
Abstract
Allogeneic hematopoietic cell transplantation is a curative procedure for hematologic malignancies but is associated with a significant risk of non-relapse mortality (NRM). The Hematopoietic Cell Transplantation- Comorbidity Index (HCT-CI) is a prognostic tool that discriminates this risk in all age groups. A recent survey of transplant physicians demonstrated that 79% of pediatric providers used the HCT-CI infrequently, and most reported concerns about its applicability in the younger population. We conducted a retrospective study using the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the impact of expanded HCT-CI definitions on NRM in pediatric and young adult patients with hematologic malignancies. We included 5,790 patients <40 years old receiving allogeneic transplant between 2008 and 2017 to examine broader definitions of comorbidities in the HCT-CI, including history of mechanical ventilation and fungal infection, estimated glomerular filtration rate (eGFR), and body mass index (BMI) percentiles. Multivariable Fine-Gray models were created to determine the effect of each HCT-CI defining comorbidity and its modification on NRM, and were utilized to develop two novel risk scores. We next developed the expanded HCT-CI for children and young adults (youth with malignancies; expanded ymHCT-CI), where 23% patients had an increased comorbidity score, compared to the HCT-CI. Comorbidities with hazard ratio (HR) <1.2 were then removed to create the simplified HCT-CI for children and young adults (youth with malignancies; simplified ymHCT-CI), which demonstrated higher scores corresponded to a greater risk of NRM (p<0.001). These novel comorbidity indices with broader definitions are more relevant to pediatric and young adult patients, and prospective studies are needed to validate these in the younger patient population. It remains to be seen if the development of these pediatric-specific and practical risk indices increases their utilization by the pediatric transplant community.
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Expanded HCT-CI Definitions Capture Comorbidity Better for Younger Patients of Allogeneic HCT for Non-Malignant Diseases
Broglie, L., Friend, B. D., Chhabra, S., Logan, B. R., Bupp, C., Schiller, G., Savani, B. N., Stadtmauer, E., Abraham, A. A., Aljurf, M., et al
Transplantation and cellular therapy. 2022
Abstract
Allogeneic hematopoietic cell transplantation (HCT) can cure many non-malignant conditions but concern for morbidity and mortality remains. To help physicians estimate patient-specific transplant mortality risk, the HCT comorbidity index (HCT-CI) is used. However, paediatric physicians use the HCT-CI less frequently than adult counterparts. We used the Center for International Blood and Marrow Transplant Research database to expand the HCT-CI comorbidity definitions to be more inclusive of children, adolescents and young adults (AYA) patients, adding history of mechanical ventilation, history of invasive fungal infection, assessment of chronic kidney disease (CKD) by estimated glomerular filtration rate, expanding the definition of obesity, and adding an underweight category. A total of 2,815 children and AYAs (<40yo) who received first allogeneic HCT for non-malignant diseases from 2008-2017 were included to create an expanded youth non-malignant HCT-CI (expanded ynHCT-CI) and a simplified non-malignant (simplified ynHCT-CI) HCT-CI. The expanded comorbidities occurred frequently - history of mechanical ventilation (9.6%), history of invasive fungal infection (5.9%), mild CKD (12.2%), moderate/severe CKD (2.1%), obesity (10.9%), underweight (14.5%). 39% of patients had an increase in their comorbidity score using the expanded ynHCT-CI, leading to a redistribution of scores: ynHCT-CI score 0 (35%), 1-2 (36.4%), and ≥3 (28.6%). Patients with an increase in their comorbidity score had an increased hazard of mortality compared to those whose score remained the same (HR 1.41, 95% CI 1.01-1.98). Modifications to the HCT-CI can benefit children and AYA patients with non-malignant diseases, creating a risk assessment tool that is clinically relevant and better captures comorbidity in this younger population.
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4.
Neighborhood-Poverty and Pediatric Allogeneic Hematopoietic Cell Transplantation Outcomes: A CIBMTR Analysis
Bona, K., Brazauskas, R., He, N., Lehmann, L. E., Abdel-Azim, H., Ahmed, I., Al-Homsi, A. S., Aljurf, M., Arnold, S. D., Badawy, S. M., et al
Blood. 2020
Abstract
Social determinants of health, including poverty, contribute significantly to health outcomes in the United States, yet their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood-poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We assembled two pediatric cohorts who received a first, allogeneic HCT from 2006-2015 at age ≤18 years; including 2053 children with malignant disease and 1696 children with non-malignant disease. Neighborhood-poverty exposure was defined a priori per U.S. Census definition as living in a high-poverty ZIP code (>=20% of persons below 100% Federal Poverty Level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS) defined as time from HCT until death from any cause. Secondary outcomes included relapse and transplant-related mortality (TRM) in malignant disease, acute and chronic GVHD, and infection in the first 100 days post-HCT. Among children transplanted for non-malignant disease, neighborhood-poverty was not associated with any HCT outcome. Among children transplanted for malignant disease, neighborhood-poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplant outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared to those with private insurance. These data suggest opportunities for future investigation of household-level poverty exposures on HCT outcomes in pediatric malignant disease to inform care delivery interventions.
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5.
Subsequent neoplasms and late mortality in children undergoing allogeneic transplantation for nonmalignant diseases
Kahn, J. M., Brazauskas, R., Tecca, H. R., Bo-Subait, S., Buchbinder, D., Battiwala, M., Flowers, M. E. D., Savani, B. N., Phelan, R., Broglie, L., et al
Blood advances. 2020;4(9):2084-2094
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Abstract
We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.
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Comprehensive Prognostication in Critically Ill Pediatric Hematopoietic Cell Transplant Patients: Results from Merging the Center for International Blood and Marrow Transplant Research (CIBMTR) and Virtual Pediatric Systems (VPS) Registries
Zinter, M. S., Logan, B. R., Fretham, C., Sapru, A., Abraham, A., Aljurf, M. D., Arnold, S. D., Artz, A., Auletta, J. J., Chhabra, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Critically ill pediatric allogeneic hematopoietic cell transplant (HCT) patients may benefit from early and aggressive interventions aimed at reversing the progression of multiorgan dysfunction. Therefore, we evaluated 25 early risk-factors for PICU mortality in order to improve mortality prognostication. We merged the Virtual Pediatric Systems (VPS, LLC) and Center For International Blood and Marrow Transplant Research (CIBMTR) databases and analyzed 936 critically ill patients ≤21 years of age who had undergone allogeneic HCT and subsequently required PICU admission between January 1, 2009 and December 31, 2014. Of 1,532 PICU admissions, the overall PICU mortality rate was 17.4% (95% CI 15.6%-19.4%) but was significantly higher for patients requiring mechanical ventilation (44.0%), renal replacement therapy (56.1%), or extracorporeal life support (77.8%). Mortality estimates increased significantly the longer that patients remained in the PICU. Of 25 HCT- and PICU-specific characteristics available at/near the time of PICU admission, moderate/severe pre-HCT renal injury, pre-HCT recipient cytomegalovirus (CMV) seropositivity, <100 day interval between HCT and PICU admission, HCT for underlying Acute Myeloid Leukemia (AML), and greater admission organ dysfunction as approximated by the PRISM-3 score were each independently associated with PICU mortality. A multivariable model using these components identified that patients in the top quartile of risk had three times greater mortality than other patients (35.1% vs. 11.5%, p<0.001, classification accuracy 75.2%, 95% CI 73.0-77.4%). These data improve our working knowledge of the factors influencing the progression of critical illness in pediatric allogeneic HCT patients. Future investigation aimed at mitigating the effect of these risk-factors is warranted.
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7.
Survival Trends in Infants Undergoing Allogeneic Hematopoietic Cell Transplant
Parikh, S. H., Satwani, P., Ahn, K. W., Sahr, N. A., Fretham, C., Abraham, A. A., Agrawal, V., Auletta, J. J., Abdel-Azim, H., Copelan, E., et al
JAMA pediatrics. 2019;:e190081
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Abstract
Importance: Studies demonstrating improved survival after allogeneic hematopoietic cell transplant generally exclude infants. Objective: To analyze overall survival trends and other outcomes among infants who undergo allogeneic hematopoietic cell transplant. Design, Setting, and Participants: In this cohort study, we used time-trend analysis to evaluate 3 periods: 2000 through 2004, 2005 through 2009, and 2010 through 2014. The study was conducted in a multicenter setting through the Center for International Blood and Marrow Transplant Research, which is made up of a voluntary working group of more than 450 transplant centers worldwide. Two groups of infants aged 1 year or younger in 2 cohorts were included: those with malignant conditions, such as leukemia, and those with nonmalignant disorders, including immunodeficiencies. Data analysis was conducted from July 2017 to December 2018. Exposures: Allogeneic hematopoietic cell transplant. Main Outcomes and Measures: Survival trends, disease relapse, and toxicity. Results: A total of 2498 infants with a median age of 7 months (range, <1-12 months) were included. In the nonmalignant cohort (n = 472), survival rates improved from the first to the second period (hazard ratio, 0.77 [95% CI, 0.63-0.93]; P = .007) but did not change after 2004. Compared with infants with nonmalignant diseases (n = 2026; 3-year overall survival: 2000-2004, 375/577 [65.0%]; 2005-2009, 503/699 [72.0%]; and 2010-2014, 555/750 [74.0%]), those with malignant conditions had poorer survival rates, without improvement over time (3-year overall survival: 2000-2004, 109/199 [54.8%]; 2005-2009, 104/161 [64.6%]; and 2010-2014, 66/112 [58.9%]). From 2000 through 2014, relapse rates increased in infants with malignant conditions (3-year relapse rate: 2000-2004, 19% [95% CI, 14%-25%]; 2005-2009, 23% [95% CI, 17%-30%]; 2010-2014, 36% [95% CI, 27%-46%]; P = .01). Sinusoidal obstruction syndrome was frequent, occurring with a cumulative incidence of 13% (95% CI, 11%-16%) of infants with nonmalignant diseases and 32% (95% CI, 22%-42%) of those with malignant diseases. Generally, recipients of human leukocyte antigen-identical sibling bone marrow grafts had the best outcomes. Conclusions and Relevance: Survival rates have not improved for infants with malignant diseases over the 15-year study period. Infants with nonmalignant diseases had improved survival rates in the earlier but not the later study period. Higher relapses for the malignant cohort and toxicities for all infants remain significant challenges. Strategies to reduce relapse and toxicity and optimize donor and graft selection may improve outcomes in the future.
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The impact of the graft-versus-leukemia effect on survival in acute lymphoblastic leukemia
Yeshurun, M., Weisdorf, D., Rowe, J. M., Tallman, M. S., Zhang, M. J., Wang, H. L., Saber, W., de Lima, M., Sandmaier, B. M., Uy, G., et al
Blood advances. 2019;3(4):670-680
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Abstract
Allogeneic hematopoietic cell transplant is a potential curative therapy for acute lymphoblastic leukemia (ALL). Delineating the graft-versus-leukemia (GVL) effect as a function of graft-versus-host disease (GVHD) offers the potential to improve survival. We examined 5215 transplant recipients with ALL reported to the Center for International Blood and Marrow Transplant Research registry. Overall survival (OS) was compared according to the presence and severity of GVHD and evaluated in 3 cohorts: 2593 adults in first or second complete remission (CR1/CR2), 1619 pediatric patients in CR1/CR2, and 1003 patients with advanced (CR ≥3 or active disease) ALL. For patients in CR1/CR2, development of acute GVHD (aGVHD) or chronic GVHD (cGVHD) was associated with lower risk of relapse than no GVHD (hazard ratio [HR], 0.49-0.69). Patients with advanced ALL developing grades III and IV aGVHD or cGVHD were also at lower risk of relapse (HRs varied from 0.52 to 0.67). Importantly, adult and children in CR1/CR2 with grades I and II aGVHD without cGVHD experienced the best OS compared with no GVHD (reduction of mortality with HR, 0.83-0.76). Increased nonrelapse mortality accompanied grades III and IV aGVHD (HRs varied from 2.69 to 3.91) in all 3 cohorts and abrogated any protection from relapse, resulting in inferior OS. Patients with advanced ALL had better OS (reduction in mortality; HR, 0.69-0.73) when they developed cGVHD with or without grades I and II aGVHD. In conclusion, GVHD was associated with an increased GVL effect in ALL. GVL exerted a net beneficial effect on OS only if associated with low-grade aGVHD in CR1/CR2 or with cGVHD in advanced ALL.
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Predictors of lost to follow-up among pediatric and adult hematopoietic cell transplant survivors: A report from the Center for International Blood and Marrow Transplant Research
Buchbinder, D., Brazauskas, R., Bo-Subait, K., Ballen, K., Parsons, S., John, T., Hahn, T., Sharma, A., Steinberg, A., D'Souza, A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
BACKGROUND Follow-up is integral for hematopoietic cell transplant (HCT) care to ensure surveillance and intervention for complications. We characterized the incidence of, and predictors for, being lost to follow-up. METHODS Two-year survivors of first allogeneic (10,367 adults and 3,865 children) or autologous (7,291 adults and 467 children) HCT for malignant/non-malignant disorders from 2002-2013 reported to the Center for International Blood and Marrow Transplant Research were selected. The cumulative incidence of being lost to follow-up (defined as having missed 2 consecutive follow-up reporting periods) was calculated. Marginal Cox models (adjusted for center effect) were fit to evaluate predictors. RESULTS The 10-year cumulative incidence of being lost to follow-up among adult allogeneic and autologous HCT survivors was 13% (95% CI, 12-14) and 15% (95% CI, 14-16), respectively. Among pediatric HCT survivors, estimates were 25% (95% CI, 24-27) and 24% (95% CI, 20-29), respectively. In adult allogeneic HCT survivors, younger age, non-malignant disease, public/no insurance (reference: private), living farther from the HCT center, and being unmarried were associated with being lost to follow-up. For adult autologous HCT survivors, older age and testicular/germ cell tumor (reference: non-Hodgkin lymphoma) were associated with greater risk of being lost to follow-up. Among pediatric allogeneic HCT survivors, older age, public/no insurance (reference: private), and non-malignant disease were associated with being lost to follow-up. Among pediatric autologous HCT survivors, older age was associated with greater risk of being lost to follow-up. CONCLUSION Follow-up focusing on minimizing attrition in high-risk groups is needed to ensure surveillance for late effects.
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GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia
Mehta, R. S., Holtan, S. G., Wang, T., Hemmer, M. T., Spellman, S. R., Arora, M., Couriel, D. R., Alousi, A. M., Pidala, J., Abdel-Azim, H., et al
Blood advances. 2019;3(9):1441-1449
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Abstract
We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.