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[Preprint]. 2023 Aug 5:2023.07.31.23293444.

doi: 10.1101/2023.07.31.23293444.

Critical Illness Risk and Long-Term Outcomes Following Intensive Care in Pediatric Hematopoietic Cell Transplant Recipients

Matt S Zinter^{1

2}, Ruta Brazauskas³, Joelle Strom³, Stella Chen³, Stephanie Bo-Subait³, Akshay Sharma⁴, Amer Beitinjaneh⁵, Dimana Dimitrova⁶, Greg Guilcher⁷, Jaime Preussler⁸, Kasiani Myers⁹, Neel S Bhatt¹⁰, Olle Ringden¹¹, Peiman Hematti³, Robert J Hayashi¹², Sagar Patel¹³, Satiro Nakamura De Oliveira¹⁴, Seth Rotz¹⁵, Sherif M Badawy¹⁶, Taiga Nishihori¹⁷, David Buchbinder¹⁸, Betty Hamilton¹⁵, Bipin Savani¹⁹, Hélène Schoemans²⁰, Mohamed Sorror¹⁰, Lena Winestone², Christine Duncan²¹, Rachel Phelan³, Christopher C Dvorak²

Affiliations

¹ Department of Pediatrics, Division of Critical Care Medicine, University of California, San Francisco, San Francisco, CA, USA.
² Department of Pediatrics, Division of Allergy, Immunology, and BMT, University of California, San Francisco, San Francisco, CA, USA.
³ Medical College of Wisconsin, Milwaukee, WI, USA.
⁴ St. Jude Children's Research Hospital, Memphis, TN, USA.
⁵ University of Miami, Miami, FL, USA.
⁶ National Institutes of Health, National Cancer Institute, Bethesda, MD, USA.
⁷ Alberta Children's Hospital, Alberta, Canada.
⁸ National Marrow Donor Program/Be The Match, Minneapolis, MN, USA.
⁹ Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁰ Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹¹ Karolinska Institutet, Karolinska University Hospital, Huddinge, The Netherlands.
¹² Washington University in St. Louis, St. Louis, MO, USA.
¹³ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁴ University of California, Los Angeles, Los Angeles, CA, USA.
¹⁵ Cleveland Clinic, Cleveland, OH, USA.
¹⁶ Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁷ Moffitt Cancer Center, Tampa, FL, USA.
¹⁸ Children's Hospital of Orange County, Orange, CA, USA.
¹⁹ Vanderbilt University Medical Center, Nashville, TN, USA.
²⁰ University Hospital Gasthuisberg, Leuven, Belgium.
²¹ Dana Farber Cancer Center, Boston, MA, USA.

PMID: 37577706
PMCID: PMC10418579
DOI: 10.1101/2023.07.31.23293444

Critical Illness Risk and Long-Term Outcomes Following Intensive Care in Pediatric Hematopoietic Cell Transplant Recipients

Matt S Zinter et al. medRxiv. 2023.

[Preprint]. 2023 Aug 5:2023.07.31.23293444.

doi: 10.1101/2023.07.31.23293444.

Authors

Affiliations

¹ Department of Pediatrics, Division of Critical Care Medicine, University of California, San Francisco, San Francisco, CA, USA.
² Department of Pediatrics, Division of Allergy, Immunology, and BMT, University of California, San Francisco, San Francisco, CA, USA.
³ Medical College of Wisconsin, Milwaukee, WI, USA.
⁴ St. Jude Children's Research Hospital, Memphis, TN, USA.
⁵ University of Miami, Miami, FL, USA.
⁶ National Institutes of Health, National Cancer Institute, Bethesda, MD, USA.
⁷ Alberta Children's Hospital, Alberta, Canada.
⁸ National Marrow Donor Program/Be The Match, Minneapolis, MN, USA.
⁹ Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁰ Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹¹ Karolinska Institutet, Karolinska University Hospital, Huddinge, The Netherlands.
¹² Washington University in St. Louis, St. Louis, MO, USA.
¹³ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁴ University of California, Los Angeles, Los Angeles, CA, USA.
¹⁵ Cleveland Clinic, Cleveland, OH, USA.
¹⁶ Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁷ Moffitt Cancer Center, Tampa, FL, USA.
¹⁸ Children's Hospital of Orange County, Orange, CA, USA.
¹⁹ Vanderbilt University Medical Center, Nashville, TN, USA.
²⁰ University Hospital Gasthuisberg, Leuven, Belgium.
²¹ Dana Farber Cancer Center, Boston, MA, USA.

PMID: 37577706
PMCID: PMC10418579
DOI: 10.1101/2023.07.31.23293444

Update in

Intensive care risk and long-term outcomes in pediatric allogeneic hematopoietic cell transplant recipients.
Zinter MS, Brazauskas R, Strom J, Chen S, Bo-Subait S, Sharma A, Beitinjaneh A, Dimitrova D, Guilcher G, Preussler J, Myers K, Bhatt NS, Ringden O, Hematti P, Hayashi RJ, Patel S, De Oliveira SN, Rotz S, Badawy SM, Nishihori T, Buchbinder D, Hamilton B, Savani B, Schoemans H, Sorror M, Winestone L, Duncan C, Phelan R, Dvorak CC. Zinter MS, et al. Blood Adv. 2024 Feb 27;8(4):1002-1017. doi: 10.1182/bloodadvances.2023011002. Blood Adv. 2024. PMID: 38127268 Free PMC article.

Abstract

Background: Allogeneic hematopoietic cell transplantation (HCT) can be complicated by the development of organ toxicity and infection necessitating intensive care. Risk factors for intensive care admission are unclear due to heterogeneity across centers, and long-term outcome data after intensive care are sparse due to a historical paucity of survivors.

Methods: The Center for International Blood and Marrow Transplant Research (CIBMTR) was queried to identify patients age ≤21 years who underwent a 1^st allogeneic HCT between 2008-2014 in the United States or Canada. Records were cross-referenced with the Virtual Pediatric Systems pediatric ICU database to identify intensive care admissions. CIBMTR follow-up data were collected through the year 2020.

Result: We identified 6,995 pediatric HCT patients from 69 HCT centers, of whom 1,067 required post-HCT intensive care. The cumulative incidence of PICU admission was 8.3% at day +100, 12.8% at 1 year, and 15.3% at 5 years post HCT. PICU admission was linked to younger age, lower median zip code income, Black or multiracial background, pre-transplant organ toxicity, pre-transplant CMV seropositivity, use of umbilical cord blood and/or HLA-mismatched allografts, and the development of post-HCT graft-versus-host disease or malignancy relapse. Among PICU patients, survival to ICU discharge was 85.7% but more than half of ICU survivors were readmitted to a PICU during the study interval. Overall survival from the time of 1^st PICU admission was 52.5% at 1 year and 42.6% at 5 years. Long-term post-ICU survival was worse among patients with malignant disease (particularly if relapsed), as well as those with poor pre-transplant organ function and alloreactivity risk-factors. In a landmark analysis of all 1-year HCT survivors, those who required intensive care in the first year had 10% lower survival at 5 years (77.1% vs. 87.0%, p<0.001) and developed new dialysis-dependent renal failure at a greater rate (p<0.001).

Conclusions: Intensive care management is common in pediatric HCT patients. Survival to ICU discharge is high, but ongoing complications necessitate recurrent ICU admission and lead to a poor 1-year outcome in many patients. Together, these data suggest an ongoing burden of toxicity in pediatric HCT patients that continues to limit long-term survival.

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Figures

**Figure 1:**
(A) Inclusion/exclusion flow diagram. (B) Cumulative incidence of PICU admission after allogeneic HCT. (B) Factors independently associated with post-HCT PICU admission in multivariable competing risk-regression model.

**Figure 2:**
(A) Kaplan Meier estimates of overall survival from the time of PICU admission for all patients (top left) and malignant vs. non-malignant patients (top middle). Cumulative incidence of treatment-related mortality (bottom left) and relapse (bottom middle) among patients transplanted for malignancy are also shown. (B) Factors independently associated with long-term survival from the time of PICU admission to last follow-up in multivariable Cox regression.

**Figure 3:**
(A) Landmark analysis of only patients surviving to HCT day +365. Kaplan Meier estimates of overall survival from transplant day +365 for all patients (top left), those with malignant disease (top middle), and those with non-malignant disease (bottom left), stratified by need for intensive care in the first year post-HCT. Cumulative incidence of treatment-related mortality (bottom middle) among patients transplanted for malignancy is also shown. (B) Among those alive at HCT day +365, factors independently associated with long-term survival from transplant day +365 to last follow-up in multivariable Cox regression.

See this image and copyright information in PMC

References

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This is a preprint.

Critical Illness Risk and Long-Term Outcomes Following Intensive Care in Pediatric Hematopoietic Cell Transplant Recipients

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Critical Illness Risk and Long-Term Outcomes Following Intensive Care in Pediatric Hematopoietic Cell Transplant Recipients

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