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\begin{document}

\title{The Impact of Graft-Versus-Host Disease on Survival in Children with
Non-Malignant Disorders Receiving Allogeneic Hematopoietic Cell
Transplant}



\author[1]{Biljana Horn}%
\author[1]{Paul Castillo}%
\author[1]{Mustafa Hanif}%
\author[2]{Jorge GalvezSilva}%
\author[3]{Edward Ziga}%
\author[3]{Warren Alperstein}%
\author[4]{Micahel Joyce}%
\author[1]{John Fort}%
\author[5]{Gauri Sunkerset}%
\author[5]{Benjamin Oshrine}%
\author[1]{Jessica Cline}%
\author[1]{Fan Yang}%
\author[1]{Jing Zhao}%
\author[5]{Deepak Chellapandian}%
\affil[1]{University of Florida}%
\affil[2]{Nicklaus Children's Hospital}%
\affil[3]{University of Miami Miller School of Medicine}%
\affil[4]{Nemours Children's Health System}%
\affil[5]{Johns Hopkins All Children's Hospital}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Abstract Background: Graft-versus-host disease (GVHD) is a common and
undesirable complication of hematopoietic cell transplant (HCT) for
non-malignant disorders (NMD). Understanding the incidence and risk
factors for GVHD in children with NMD is an important step in developing
strategies for its prevention. Study Design: This is a retrospective,
registry, study that included children with NMD receiving HCT in 5
centers in Florida between 2010 and 2019. Results: Among 183 patients
evaluable for GVHD, acute GVHD (aGVHD) grades I, II, III, and IV were
present in 18\%, 12.6\%, 3.8\% and 5.5\% of patients, respectively.
Limited and extensive chronic GVHD (cGVHD), were observed in 8.7\% and
12.6\% of patients. Patients with aGVHD grade III/IV had significantly
lower 3-year survival rates than those without aGVHD, or those with
aGVHD grade I/II (52.9\% {[}95\% confidence interval (CI) 34-83{]} vs.
90.1\% {[}95\% CI 84-96{]}, vs. 98.1\% {[}95\%CI 95-100{]},
p\textless{}0.001). Patients without cGVHD and those with limited and
extensive cGVHD had 3-year survival rates of 88.9\% {[}95\%CI 84-94{]},
91.7\% {[}95\%CI 77-100{]}, and 84.8\% {[}95\%CI 70-100{]},
respectively, log rank p=0.3. Receiving transplant from an
HLA-mismatched unrelated donor (MMUD), as compared to a matched related
donor (MRD), increased the risk for aGVHD grade III/IV (Odds ratio 10.4
{[}95\% CI 2.5-47.6{]}). There were no cases of aGVHD grade III/IV among
recipients of mismatched related/haploidentical transplants.
Conclusions: Grade III/IV aGVHD, which significantly reduced overall
survival, was reported in 9.3\% of children with NMD receiving HCT. Risk
factors included HCT from a MMUD but not mismatched related donors.%
\end{abstract}%



\sloppy


\textbf{The Impact of Graft-Versus-Host Disease on Survival in Children
with Non-Malignant Disorders Receiving Allogeneic Hematopoietic Cell
Transplant}

Biljana Horn, MD\textsuperscript{1}\textsubscript{,} Paul Castillo,
MD\textsuperscript{1}, Mustafa Hanif\textsuperscript{1}, Jorge Galvez
Silva, MD\textsuperscript{3}, Edward Ziga, MD\textsuperscript{4}, Warren
Alperstein, MD\textsuperscript{4}, Michael Joyce, MD,
PhD\textsuperscript{5}, John Fort, MD\textsuperscript{1}, Gauri
Sunkersett, DO\textsuperscript{2}, Benjamin Oshrine,
MD\textsuperscript{2}, Jessica Cline, BS\textsuperscript{1}, Fan Yang,
MS\textsuperscript{1}, Jing Zhao, PhD.MS\textsuperscript{1} and Deepak
Chellapandian, MD MBBS\textsuperscript{2}

Affiliations:

(1) University of Florida, Gainesville, FL

(2) Center for Cell and Gene Therapy for Non Malignant-Conditions, Blood
and Marrow Transplant Program, Cancer \& Blood Disorders Institute,
Johns Hopkins All Children's Hospital, St Petersburg, FL; (3) Nicklaus
Children's Hospital, Miami, FL

(4) Pediatric Hematology and Oncology, University of Miami School of
Medicine, Miami, FL (5) Nemours Children's Clinic and Wolfson Children's
Hospital, Jacksonville, FL

Corresponding Author:

Email: Biljana Horn; e-mail: Biljana.horn@ufl.edu,

1600 SW Archer Avenue, Gainesville, FL 32610

Phone (mobile) 415-215-6930, FAX:352 294 8091

Article Type: Research Article

Word Count: abstract 246

Word Count: main text 2571

Tables: 3, Figures: 2, References: 21, Supporting files: 0

Short Title: GVHD in Children with Non-Malignant Disorders

Key Words: GVHD, pediatric HCT, non-malignant disorders, Florida
consortium

Abbreviations used in the manuscript:\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
ATG & Anti-thymocyte globulin\tabularnewline
\midrule
\endhead
BM & Bone Marrow\tabularnewline
CIBMTR & Center for International Blood and Marrow Transplant
Research\tabularnewline
FPBCC & Florida Pediatric Bone Marrow Transplant and Cell Therapy
Consortium\tabularnewline
GVHD, aGVHD, cGVHD & Graft-versus-host disease, acute graft versus-host
disease, chronic graft-versus-host disease\tabularnewline
HCT & Hematopoietic cell transplant\tabularnewline
HLA & Human leukocyte antigen\tabularnewline
MMUD & Mismatched unrelated donor\tabularnewline
MMRD & Mismatched related donor\tabularnewline
MRD & Matched related donor\tabularnewline
MUD & Matched unrelated donor\tabularnewline
NMD & Non-malignant disorders\tabularnewline
OR & Odds ratio\tabularnewline
OS & Overall survival\tabularnewline
PB & Peripheral blood\tabularnewline
UCB & Umbilical cord blood\tabularnewline
\bottomrule
\end{longtable}

Previous Presentations: Abstract presentation during the virtual
Transplantation and Cellular Therapy Meeting, February 8-12, 2021 under
title: Risk of Clinically Significant Graft-Versus-Host Disease in
Children Receiving Allogeneic Hematopoietic Cell Transplant (HCT) for
Non-Malignant Disorders in Florida (2010-2019).



\textbf{Abstract}

\textbf{Background:}

Graft-versus-host disease (GVHD) is a common and undesirable
complication of hematopoietic cell transplant (HCT) for non-malignant
disorders (NMD). Understanding the incidence and risk factors for GVHD
in children with NMD is an important step in developing strategies for
its prevention.

\textbf{Study Design:}

This is a retrospective, registry, study that included children with NMD
receiving HCT in 5 centers in Florida between 2010 and 2019.

\textbf{Results:}

Among 183 patients evaluable for GVHD, acute GVHD (aGVHD) grades I, II,
III, and IV were present in 18\%, 12.6\%, 3.8\% and 5.5\% of patients,
respectively. Limited and extensive chronic GVHD (cGVHD), were observed
in 8.7\% and 12.6\% of patients. Patients with aGVHD grade III/IV had
significantly lower 3-year survival rates than those without aGVHD, or
those with aGVHD grade I/II (52.9\% {[}95\% confidence interval (CI)
34-83{]} vs. 90.1\% {[}95\% CI 84-96{]}, vs. 98.1\% {[}95\%CI 95-100{]},
p\textless{}0.001). Patients without cGVHD and those with limited and
extensive cGVHD had 3-year survival rates of 88.9\% {[}95\%CI 84-94{]},
91.7\% {[}95\%CI 77-100{]}, and 84.8\% {[}95\%CI 70-100{]},
respectively, log rank \emph{p} =0.3. Receiving transplant from an
HLA-mismatched unrelated donor (MMUD), as compared to a matched related
donor (MRD), increased the risk for aGVHD grade III/IV (Odds ratio 10.4
{[}95\% CI 2.5-47.6{]}). There were no cases of aGVHD grade III/IV among
recipients of mismatched related/haploidentical transplants.

\textbf{Conclusions:}

Grade III/IV aGVHD, which significantly reduced overall survival, was
reported in 9.3\% of children with NMD receiving HCT. Risk factors
included HCT from a MMUD but not mismatched related donors.

\textbf{Introduction}

Allogeneic hematopoietic cell transplantation is used to treat a variety
of malignant and non-malignant hematologic disorders. (1,2) In patients
with NMD, rejection, treatment-related mortality, and GVHD are the main
obstacles to favorable outcomes.

Graft-versus-host disease is an immunologically mediated process
involving donor immune cell responses against major or minor
histocompatibility antigens of the recipient. Acute GVHD is driven by
donor's lymphocytes and inflammatory cytokine cascade, while chronic
GVHD involves inflammation, immune dysregulation and fibrosis. (3,4) In
children with malignant disorders, graft-versus-host effect may
correlate with graft-versus-leukemia effect and contribute to reduction
of relapse; (5,6) however, there is no benefit of GVHD in patients with
NMD, and any degree of GVHD in this population is considered an
undesirable iatrogenic effect. Understanding the incidence and risk
factors for GVHD in children with NMD is in important step in developing
strategies for its prevention.

In this report we describe the incidence of acute and chronic GVHD in a
contemporary cohort of children receiving HCT for NMD, describe survival
outcomes based on GVHD grades, and identify risk factors for aGVHD grade
III/IV, which correlated with inferior survival.

\textbf{Study Design}

For this retrospective, registry study, we gathered data from the
Florida Pediatric Bone Marrow Transplant and Cell Therapy Consortium
(FPBCC). The objectives of FPBCC are to identify pediatric HCT best
practices and improve survival of children receiving HCT in Florida.
FBPCC participation involves monthly virtual meetings, participation in
quality improvement projects, sharing data for retrospective trials, and
developing consortium-wide prospective clinical trials. FPBCC was
founded in 2018 and comprises 5 of the 6 pediatric transplant programs
in the state of Florida, USA. All FPBCC participating centers signed
memoranda of understanding and data use agreements and obtained
institution-specific IRB approvals for this retrospective data analysis.
All patients have signed the informed consent for data reporting.
Transplant centers report detailed data on consecutive hematopoietic
cell transplantations to the statistical center of the Center for
International Blood and Marrow Transplant Research (CIBMTR), and
compliance with this reporting is monitored by on-site audits. Data from
participating centers were downloaded from the enhanced data back to
center platform of CIBMTR and forwarded to the FPBCC statistical center
at the University of Florida (Gainesville, FL, USA), where data were
combined into a single set and analyzed.

We describe characteristics of pediatric HCT recipients, including
gender, age, race, performance score, diagnosis, type of transplant, and
number of pre-transplant comorbidities. Transplant characteristics
consist of type of donor, stem cell source, Human Leukocyte Antigen
(HLA) match, conditioning regimen, and regimen intensity. Outcomes data
include length of survival, cause of death, and incidence and grade of
GVHD. Our data set included information on timing and use of second
transplant; however, reasoning (e.g. early or late graft rejection) for
second transplant was not available and the dataset did not contain
details of donor lymphocyte infusions or details of GVHD prophylaxis
other than the use of serotherapy. Thus patients who required the
2\textsuperscript{nd} or subsequent transplant (N=21) and those who
rejected the transplant but did not undergo a subsequent transplant
(N=3) were not included in this manuscript. Patients for whom the center
did not provide information on GVHD (N=3) were considered not-evaluable
for GVHD and excluded as well. Myeloablative regimens were defined as
those using one or more of the following: total body irradiation
\textgreater{}500 cGy for a single dose or \textgreater{}800 cGy for
fractionate, busulfan \textgreater{}7.2 mg/kg iv, melphalan
\textgreater{}150 mg/m\textsuperscript{2}, or thiotepa [?]10 mg/kg.
Reduced intensity regimens were defined as those using melphalan [?]150
mg/m\textsuperscript{2}, thiotepa \textless{}10 mg/kg, TBI
\textgreater{}200 cGy and [?]500 cGy as a single dose or [?]800 cGy
fractionated, busulfan [?]7.2 mg/kg. Non-myeloablative regimens used any
dose of ATG, fludarabine, cyclophosphamide, or TBI[?]200 cGy. (7) Fully
HLA-matched unrelated bone marrow (BM) or peripheral blood (PB) donors
were matched at A, B, C, and DRB1 antigens by high-resolution typing.
For umbilical cord blood (UCB) donors, full match was defined as 6/6
HLA-antigen match (A, B, DRB1) by either low or high resolution. A
related donor was considered haploidentical if [?] 2 different antigens
(A, B, C, or DRB1) were mismatched. CIBMTR gathers and reports the
highest grade of acute GVHD by one year post transplant following
criteria published by Przepiorka et al. (8) Although currently CIBMTR
gathers data on individual organ involvement with cGVHD based on NIH
Consensus Criteria, 2014, the data available through our platform
contained only information on extent of cGVHD by one year post
transplant.

cGVHD was reported as limited or extensive based on definition by
Shulman et al. (9) Limited cGVHD includes only localized skin
involvement and/or liver dysfunction, while any other organ involvement
is considered extensive.

\textbf{Statistical analyses}

Descriptive statistics were used for summarizing patient and transplant
characteristics. Overall survival (OS) was defined as the duration of
time from transplant to time of death or the date of the last follow-up
reported to the CIBMTR database. The Kaplan-Meier method was used to
estimate overall survival and the log-rank test was used to examine the
effect of acute and chronic GVHD on overall survival. Odds ratio (OR)
analysis was used to identify factors associated with the development of
aGVHD grade III/IV. Analyses were performed with SPSS\selectlanguage{ngerman}® statistical
program version 25-26 (IBM Corp., Armonk, N.Y., USA) and R Core Team,
2020.

\textbf{Results}

\emph{Patient characteristics}

Table 1 Patient and transplant characteristics describes details of 183
children undergoing first allogeneic HCT for NMD in Florida during
2010-2019, who had data on GVHD reported to CIBMTR. The most common
diagnoses included sickle cell disease (24.0\%), severe aplastic anemia
(21.9\%), primary immunodeficiencies including severe combined
immunodeficiency (24.1\%), thalassemia (11.5\%) and bone-marrow failure
syndromes (8.2\%). Median age of children was 7 years (range 0-21) with
even distribution among \textless{}3 years, 3-9 years, and \selectlanguage{english}[?]10 years of
age groups. Graft types included bone marrow (BM), umbilical cord blood
(UCB), and peripheral blood (PB) used in 69.9\%, 18.6\%, and 9.8\% of
patients, respectively. Donors were related in 53.6\% of cases and
unrelated in the rest. Fully HLA-matched donors were used in 65.6\% of
HCT, mismatched in 31.1\%, and for 3.3\% of patients the degree of match
was unknown. Conditioning regimens were myeloablative in 55.2\% of
patients, and 4.4\% of patients did not receive any conditioning, while
all other patients received non-myeloablative or reduced intensity
regimens. Low dose (200cGy) total body irradiation (TBI) was used in
7.6\% of HCT recipients. Anti-thymocyte globulin was used in
conditioning of 55.2\% of patients and alemtuzumab in 34.4\%. Rituximab
was used as part of GVHD prophylaxis by one center for a majority of
their transplant recipients, and thus 23.0\% of patients received a
single dose of rituximab during conditioning.

\emph{Survival for the entire cohort and causes of death}

Kaplan-Meier estimated overall survival for the entire cohort at 36
months was 88.5\% {[}95\% CI 84-94{]}. Twenty-three (12.6\%) patients
have died, with bacterial infections being responsible for 7 (30.4\%)
deaths, fungal infections for 1 (4.3\%), organ failures for 8 (34.8\%),
recurrence of underlying disease for 3 (13.0\%), secondary malignancy
for 1 (4.3\%), while acute and chronic GVHD were responsible for 2
deaths (8.6\%). For 1 patients (4.3\%), the cause of death was unknown.

\emph{Incidence of GVHD and survival based on GVHD grade}

Out of 183 evaluable patients, 110 (60.1\%) did not have any evidence of
aGVHD, 33 (18\%) had aGVHD grade I, 23 (12.6\%) grade II, 7 (3.8\%)
grade III, and 10 (5.5\%) grade IV. One hundred forty-four patients
(78.7\%) did not have cGVHD, 16 (8.7\%) had chronic limited, and 23
(12.6\%) had chronic extensive GVHD. Table 2 describes the incidence of
GVHD by donor relation, stem cell source and HLA-match. Patients
receiving unrelated mismatched donor BM, PB, or mismatched UCB had the
highest incidence of aGVHD (68.7\% and 63.2\%, respectively). The
incidence of aGVHD in haploidentical and MRD recipients was 36.4\% and
29.6\%, respectively. However, there was no aGVHD grade III/IV among
haploidentical HCT recipients. FIGURE 1 depicts overall survival by
acute GVHD grade and FIGURE 2 depicts overall survival by cGVHD grade.
Patients without aGVHD, aGVHD grade I/II, and aGVHD grade III/IV had
3-year survival of 90.1\% {[}95\%CI 84-96{]}, 98.1\% {[}95\%CI
95-100{]}, and 52.9\% {[}95\%CI 34-83{]}, respectively. The difference
in survival among the 3 groups was significant (log rank
p\textless{}0.0001). Patients without cGVHD and those with limited and
extensive cGVHD had 3-year survival rates of 88.9\% {[}95\%CI 84-94{]},
91.7\% {[}95\%CI 77-100{]}, and 84.8\% {[}95\%CI 70-100{]},
respectively. Neither limited nor extensive cGVHD significantly affected
3-year survival rates (log rank p=0.3).

\emph{Risk factors for development of grade III/ IV aGVHD}

Because aGVHD grade III/IV adversely affected survival, we analyzed risk
factors for its development as shown in TABLE 3 Risk factors for
developing aGVHD grade III/IV. The risk of aGVHD grade III/IV was higher
in patients receiving HLA mismatched donor transplant (OR 3.4 {[}95\%CI
1.1-11.2{]}. However, not all recipients of mismatched donor transplants
were at risk of aGVHD grade III/IV. Only the recipients of mismatched
unrelated donor HCTs comparing to MRD had an increased risk of grade
III/IV aGVHD (OR 10.4 {[}95\% CI 2.5-47.6{]}). Among recipients of \selectlanguage{english}[?]2 Ag
mismatched related donor transplants, there were no cases of aGVHD grade
III/IV. The use of mismatched cord blood donors was not associated with
slight increase in risk of aGVHD grade III/IV in comparison with MRD (OR
1.3 {[}95\% CI 0.1-8.0{]}).

\emph{Causes of death in patients with and without aGVHD grade III/IV}

At a mean follow-up, for alive patients, of 38.9 months (+-SD 25.8
months) 15/166 (9\%) and 8/17 (47\%) of patients without and with aGVHD
grade III/IV were deceased, respectively. The causes of death in
patients without and with aGVHD grade III/IV included recurrent disease
(13.3\% vs 12.5\%), organ failure (40\% vs 25\%), bacterial infection
(33\% vs 25\%), fungal infection (0 vs 12.5\%) GVHD (0\% vs 25\%),
2\textsuperscript{nd} malignancy (6.7\% vs 0\%), and unknown (6.7\% vs
0\%).

\textbf{Discussion}

We describe acute and cGVHD incidence in a contemporary cohort of
children with NMD undergoing allogenic HCT. There is abundant literature
on the incidence and risk factors for GVHD in adult and pediatric HCT
recipients with malignant disorders; however, similar reports are scarce
for children with NMD. The larger published studies describing impact of
GVHD on clinical outcomes included patients transplanted in the 1990s
(5) or included patients transplanted over several decades. (10,11)
Given changes in HCT practices, it was important to validate these
results on a contemporary cohort of patients.

Regarding incidence of GVHD in pediatric patients with NMD, our findings
are similar to findings from the Japanese transplant registry, which
included all children with NMD transplanted between 1985 and 2016. (10)
Umeda et al. reported cumulative incidences of aGVHD grade II-IV, aGVHD
grade III-IV, and cGVHD of 24\%, 9.1\% and 17.8\%, compared with 21.9\%,
9.3\% and 21.3\% in our cohort. (10)

Our data shows that aGVHD grade III/IV, which developed in 9.3\% of
children with NMD, significantly affected the overall survival, while
aGVHD grade I/II has no adverse impact on survival. Due to small numbers
of deceased patients, we could not identify significant differences in
cause of death between patients with and without aGVHD grade III/IV. The
risk of infections was similar between the 2 groups and GVHD was
considered the primary cause of death in 2 patients. Similar to previous
reports, we could not document significantly reduced survival rates in
children with cGVHD (5,10). Even when it does not affect survival, due
to related morbidity and impact on quality of life, any acute or cGVHD
represents an unwanted iatrogenic complication in children with NMD.

Due to genetic diversity of Florida's population, finding a fully
HLA-matched donor is difficult and 31\% of our patients received stem
cells from alternative donors such as mismatched cord blood, mismatched
unrelated donors, and mismatched related donors. Our study indicates
that only recipients of mismatched unrelated BM and PB had an increased
risk of aGVHD grade III/IV, which was related to reduced survival. The
incidence of aGVHD grade III/IV was lower in mismatched related donor
recipients than in MRD, and was similar in mismatched UCB recipients to
MRD.

Previous publications (Bertaina A et al., Zecca et al., Anurathapan et
al.) reported absence of aGVHD grade III/IV in haploidentical transplant
recipients, regardless which of the 3 depletion strategies was used
(CD34 positive selection, \selectlanguage{greek}αβ \selectlanguage{english}T-cell and CD19+ cell depletion, or in vivo
T-cell depletion with post-transplant cyclophosphamide). (13-15)

In our previous analysis of data from the FPBCC, we observed inferior
survival of children with NMD receiving HCT from mismatched unrelated
donors, including mismatched cord blood, and we recommended that use of
mismatched related donors be favored over mismatched unrelated BM, PB or
UCB donors. (16) Findings from this study indicate that improved methods
of GVHD prophylaxis are needed in children with NMD receiving mismatched
unrelated BM or PB. Recent literature describes use of abatacept, alpha
beta (\selectlanguage{greek}αβ\selectlanguage{english}) T-cell and CD19-cell depletion, and post-transplant
cyclophosphamide as promising methods for GVHD prophylaxis in children
with NMD. (13,17-19) However, donor selection and the approach to GVHD
prophylaxis when an HLA-matched donor is lacking, is the subject of
research and until large randomized studies are available, the
alternative donor selection and GVHD prophylaxis will likely remain
center-specific. Only 1/5 FPBCC transplant centers performed ex-vivo
T-cell depletion/CD34+ selection during the study period, and no centers
performed \selectlanguage{greek}αβ \selectlanguage{english}T-cell depletion, while all centers used post-transplant
cyclophosphamide, which was used in the majority of haploidentical HCT
recipients in this study. Post-transplant cyclophosphamide use results
in excellent outcomes and significant reduction in grade III/IV GVHD;
however, higher risk of graft failure in pediatric non-malignant
conditions and hemoglobinopathies, and post-transplant late effects
related to high dose chemotherapy warrant caution when using this method
of GVHD prophylaxis in children with NMD. (20,21) Literature indicates
that alpha beta CD3+/CD19+ cell depleted haploidentical HCT resulted in
excellent survival, low GVHD rates, and good immune reconstitution, and
this method is emerging as a promising strategy for GVHD prevention in
children with NMD. (13) However, some investigators feel that
significant myeloablation, required for T-cell depleted transplants, is
a disadvantage of this approach.

Due to its retrospective, registry nature, our study lacked some
relevant data, such as agents used for GVHD prophylaxis or method of
T-cell depletion. Although we included 10-year pediatric transplant
data, the numbers, particularly in some subgroups, are still low,
emphasizing that transplants for pediatric NMD are rare events (only
20-25 of these transplants are done annually in Florida) and that
consolidating data, not only across centers but across different NMD
diagnostic groups, is necessary in order to understand outcomes and
complications of those transplants.

\textbf{Conclusions}

Acute GVHD grade III/IV developed in 9.3\% of children undergoing HCT
for NMD, and it was related to an adverse 3-year overall survival
(52.9\% {[}95\% CI 34-83{]}). Although contributing to morbidity, grade
I/II aGVHD or cGVHD did not impact overall survival. Recipients of
mismatched unrelated BM or PB transplants, but not those of mismatched
related donor transplants or mismatched cord blood transplants, were at
a high risk for aGVHD grade III/IV. In order to reduce the incidence of
aGVHD grade III/IV and improve survival, we recommend either avoiding
mismatched unrelated donors or using novel methods for GVHD prophylaxis,
ideally done on prospective clinical trials.

\textbf{Conflict of Interest Statement}

The authors of this manuscript declare that they do not have relevant
conflicts of interest in the subject matter discussed.

\textbf{Acknowledgement}

We gratefully acknowledge the support of Dr. Douglas Rizzo, Senior
Scientific Director from CIBMTR who introduced us to the eDBtC platform.
We thank the nonprofit Children's Miracle Network for their 2018 and
2020 grants in support of FPBCC.

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  Overall survival by chronic GVHD grade Data: The data that support the
  findings of this study are available from the corresponding author
  upon a reasonable request. .
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