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Late Effects Following Pediatric HCT
Version June 18, 2014
Natural History and Biology of Long-Term Late Effects Following Hematopoietic Cell
Transplant for Childhood Hematologic Malignancies
Study Chairpersons
K. Scott Baker, MD
Christine Duncan, MD
Protocol Team
Lynnette Anderson
Kristen Barbieri
Andrew Dietz
Sangeeta Hingorani
Karina Danner Koptik
Morris Kletzel
Jerelyn Moffet
Michael Nieder
Angela R. Smith
Jeffrey Auletta
Kristen Beebe
Christopher Dvorak
David Jacobsohn
Robert Krance
Paul Martin
Willis Navarro
Michael Pulsipher
Version 1.0
June 18, 2014
NMDP IRB Approved 08/07/2014 through 07/09/2015 Late Effects Following Pediatric HCT
Version June 18, 2014
PROTOCOL SYNOPSIS
PBMTC PROTOCOL XXXX/CIBMTR 13-TLEC
Natural History and Biology of Late Effects Following Hematopoietic Cell
Transplant in Children
Sponsor: The Pediatric Blood and Marrow Transplant Consortium (PBMTC) in
collaboration with the Resource for Clinical Investigation in Blood and Marrow
Transplantation (RCI-BMT) of the Center for International Blood and Marrow Transplant
Research (CIBMTR)
Principal Investigators:
K. Scott Baker, M.D.
Christine N. Duncan, M.D.
Study Design:
This is a prospective non-therapeutic study, assessing the long-term toxicity of pediatric HCT for
hematologic malignancies. This study is a collaboration between the Pediatric Blood and Marrow
Transplant Consortium (PBMTC), the Center for International Blood and Marrow Transplant Research
(CIBMTR), the National Marrow Transplant Program (NMDP) and the Resource for Clinical Investigation
in Blood and Marrow Transplantation (RCI-BMT) of the CIBMTR. The study will enroll pediatric patients
who undergo myeloablative HCT for hematologic malignancies at PBMTC sites.
The study examines the hypothesis that survivors of pediatric HCT are at risk for late organ toxicity and
they will have identifiable biomarkers present within the first two years following HCT which will be
predictive for late adverse outcomes allowing for early identification of patients at risk.
Primary Objective
To report the incidence of chronic kidney disease (CKD), metabolic syndrome, and osteopenia at one and
two-years following allogeneic HCT for hematologic malignancy
Secondary Objectives
1. To identify prognostic risk factors for the development and progression of post-HCT CKD, metabolic
syndrome, and osteopenia at 1 and 2-years following HCT
2. To investigate potential associations of systemic hypertension as measured with intermittent blood
pressure assessment with proteinuria, acute kidney injury, and CKD at day 100,1-year, and 2-years
following HCT
3. To compare the results of GFR estimating equations based on serum cystatin C levels or serum
creatinine to GFR measured by nuclear medicine GFR and/or 24-hour creatinine clearance prior to and
at 180 days and 1 and 2-years following HCT
4. To explore potential association of the protein biomarker elafin in the urine at with the development of
CKD at 180 days and1-year and 2-years post-HCT
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5. To report levels of fasting triglycerides, low-density lipoprotein, high-density lipoprotein, insulin, and
glucose levels prior to HCT and at days 100, 1-year, and 2-years following HCT
6. To assess change in body composition including bone mineral density, body mass index, percent fat
mass and lean body mass as measured by dual-energy absorptiometry at 1-year and 2-years post-HCT
compared to pre-HCT values
7. To assess the presence of osteopenia prior to HCT and at 1-year and 2-years following HCT by x-ray in
patients unable to undergo DXA without sedation.
8. To report levels of markers of bone turnover including serum osteocalcin, bone specific alkaline
phosphatase, and urine N-telopeptide prior to HCT and at days 30, 100, 1-year, and 2-years following
HCT
9. To develop a repository for plasma and DNA to be used in future investigation of HCT-associated late
effects
Eligibility Criteria
Inclusion Criteria
1. Age less than 22 years at admission for HCT. There is no lower limit on age.
2. Planned allogeneic HCT from any donor and stem cell source. There are no study-specific criteria
for HLA-matching.
3. Disease and disease status criteria
a. Acute lymphoblastic leukemia/lymphoma in complete morphologic remission defined as a M1
marrow (<5% blasts) with no evidence of active extramedullary disease within 30 days of the
start of the conditioning regimen; OR
b. Myelodysplasia (regardless of subtype) with less than 10% marrow blasts within 30 days of the
start of the conditioning regimen; OR
c. Acute myelogenous leukemia in complete morphologic remission defined as an M1 marrow
(<5% blasts) with no evidence of extramedullary disease within 30 days of the start of the
conditioning regimen; OR
d. Juvenile myelomonocytic leukemia; OR
e. Chronic myelogenous leukemia excluding refractory blast crisis.
4. Planned myeloablative conditioning regimen, defined as a regimen including one of the following as
a backbone agent:
a. Busulfan ≥ 12.8 mg/kg total dose (IV or PO). PK-based dosing allowed, if the intent is total
overall dose ≥ 12.8 mg/kg; OR
b. Total Body Irradiation ≥ 1200 cGy fractionated; OR
c. Treosulfan ≥ 30 g/m2 total dose IV
Regimens may include other agents as long as at least one of the above criterion is met.
5. Enrollment in the following NMDP research protocols:
a. Protocol for a Research Database for Hematopoietic Cell Transplantation, Other Cellular
Therapies and Marrow Toxicity Injuries
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b. Protocol for a Research Sample Repository for Allogeneic Hematopoietic Stem Cell
Transplantation and Marrow Toxic Injuries
A subject must provide consent to both of these NMDP research protocols to be eligible for
participation in the 13-TLEC study.
6. Written informed consent document signed by patient if the age is greater than or equal to 18 years
and the patient is developmentally able to provide consent. The informed consent document is to
be signed by the parent or legal guardian if the patient’s age is less than 18 years or if the patient is
older than 18 years, but developmentally unable to provide consent. Assent will be obtained
according to the guidelines of the patient’s transplant institution.
Exclusion Criteria
1. Prior allogeneic or autologous HCT
2. Patients with renal disease prior to the start of HCT conditioning requiring the use of dialysis at the
time of enrollment and/or GFR < 60 mL/min/1.73 m2
3. Patients with osteopenia or osteoporosis treated with a bisphosphonate medication at any time prior
to enrollment
4. Patients with preexisting diabetes or hyperglycemia treated with insulin or oral hypoglycemic
medication at the time of enrollment
5. Patients with uncontrolled viral, bacterial, fungal or protozoal infection at the time of study
enrollment
6. Karnofsky performance score or Lansky Play-Performance Scale Score <60 at the time of study
enrollment
7. Known inherited or constitutional predisposition to cancer including, but not limited to Down
Syndrome, Li-Fraumeni syndrome, Fanconi Anemia, and patients with BRCA1 and BRCA2
mutations
Accrual Objective:
Three-hundred and forty subjects are projected to be enrolled.
Accrual Period:
The accrual period is 3 years.
Study Duration:
All subjects will be followed for 2 years after HCT. We expect the study duration to be 5 years.
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TABLE OF CONTENTS
Study schema .....................................................................................................................................
1.0
Background and rational .......................................................................................................
1.1 Introduction ......................................................................................................................
1.2 Post-transplant chronic kidney disease ...........................................................................
1.2.1 Albuminuria ..................................................................................................................
1.2.2 Creatinine, GFR, and cystatin C ..................................................................................
1.2.3 Renal biomarker assessment .......................................................................................
1.3 Cardio-metabolic risk .......................................................................................................
1.3.1 Metabolic syndrome and body composition .................................................................
1.3.2 Blood pressure monitoring ...........................................................................................
1.4 Skeletal late effects .........................................................................................................
1.4.1 Vitamin D deficiency .....................................................................................................
1.4.2 Dual-energy absorptiometry .........................................................................................
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2.0
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Study design .........................................................................................................................
2.1 Study overview ............................................................................................................... .
2.2 Hypotheses and study objectives ...................................................................................
2.2.1 Hypotheses ..................................................................................................................
2.2.2 Objectives ....................................................................................................................
2.3 Eligibility criteria ..............................................................................................................
2.4 Study procedures ........................................................................................................... .
2.4.1 Consent and Protocol Co-Requirements ....................................................................
2.4.2 Data collection .............................................................................................................
2.4.2.1 Pre-HCT data ............................................................................................................
2.4.2.2 Transplant specific data ............................................................................................
2.4.2.3 Post-HCT data ..........................................................................................................
2.4.3 Nuclear medicine GFR, creatinine clearance, and cystatin C ......................................
2.4.4 Blood pressure measurement ......................................................................................
2.4.5 Body composition measurement ..................................................................................
2.4.6 Metabolic marker laboratory testing .............................................................................
2.4.7 Markers of bone metabolism, 25-OH vitamin D, and parathyroid hormone .................
2.4.8 Biorepository sample collection and shipment .............................................................
3.0 Study endpoints ...........................................................................................................................
3.1 Primary endpoints ...........................................................................................................
3.1.1 Chronic kidney disease ................................................................................................
3.1.2 Metabolic syndrome .....................................................................................................
3.1.3 Osteopenia ...................................................................................................................
3.2 Secondary endpoints ......................................................................................................
3.2.1 Hypertension ................................................................................................................
3.2.2 Acute kidney injury .......................................................................................................
3.2.3 Dyslipidemia .................................................................................................................
3.2.4 Osteoporosis ................................................................................................................
3.2.5 Albuminuria ..................................................................................................................
3.2.6 Proteinuria ....................................................................................................................
3.2.7 Adiposity .......................................................................................................................
3.2.8 Obesity ..........................................................................................................................
3.2.9 Vitamin D deficiency ......................................................................................................
3.3 Tertiary endpoints .............................................................................................................
3.3.1 BMD ..............................................................................................................................
3.3.2 BMI ...............................................................................................................................
3.3.3 GFR ..............................................................................................................................
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4.0 Patient registration and enrollment ................................................................................................
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4.1 Patient registration and enrollment ...................................................................................
4.2 Schedule of required data and studies .............................................................................
4.3 Data reporting ...................................................................................................................
4.4 Adverse event reporting ....................................................................................................
4.5 Unanticipated problems ……………………………………………………………………….
4.6 Data safety and monitoring ...............................................................................................
4.6 Study monitoring ...............................................................................................................
5.0 Statistical considerations ................................................................................................................
5.1 Study design ......................................................................................................................
5.2 Primary objective ...............................................................................................................
5.3 Sample size, accrual, and study duration .........................................................................
5.4 Interim analysis and stopping guidelines ..........................................................................
5.5 Variables of interest ..........................................................................................................
5.6 Analysis of primary endpoint .............................................................................................
5.7 Analysis of secondary endpoints .......................................................................................
5.8 Analysis of tertiary endpoints .............................................................................................
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References ............................................................................................................................................
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Appendix A: Normal blood pressure in children ....................................................................................
Appendix B: BMI growth charts .............................................................................................................
Appendix C: Triglyceride and cholesterol levels ...................................................................................
Appendix D: Waist circumference .........................................................................................................
Appendix E: Body fat percentiles ..........................................................................................................
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Pre-HCT Eligibility & Enrollment
Study Schema
Pre-HCT Assessment & Studies

Baseline morbidity

Physical examination, weight, height, waist circumference, blood
pressure

Repository plasma

Calculated eGFR

GFR or creatinine clearance

Urine elafin

Renal markers

Skeletal markers

Metabolic markers

DXA or chest radiograph

Vitamin D, PTH, and calcium
HCT Conditioning
& Stem Cell Infusion
Day 30 +/- 7 days

Physical examination, weight, height, waist circumference, blood
pressure

Repository plasma

Calculated eGFR

Renal markers

Metabolic markers

Skeletal markers
Day 100 +/- 14 days

Assessment of late effects, medications, & therapeutic interventions

Physical examination, weight, height, waist circumference, blood
pressure

Repository plasma

Calculated eGFR

GFR or creatinine clearance

Urine elafin

Renal markers

Skeletal markers

Metabolic markers

Vitamin D, PTH, and calcium
Renal markers: Urine
protein and albumin; serum
and urine creatinine
Metabolic markers: Fasting
triglycerides, HDL
cholesterol, LDL
cholesterol, insulin and
glucose
Skeletal markers:
osteocalcin,
bone specific alkaline
phosphatase, urine Ntelopeptide
Day 180 +/- 21 days

Physical examination, weight, height, waist circumference,

Urine protein & albumin; creatinine (urine and serum)

Calculated eGFR

GFR or creatinine clearance

Urine elafin
1 year +/- 30 days and 2 year +/- 60 days

Assessment of late effects, medications, & therapeutic interventions

Physical examination, weight, height, waist circumference, blood
pressure

Repository plasma

Calculated eGFR

GFR or creatinine clearance

Urine elafin

Skeletal markers

Metabolic markers

DXA
7 
Vitamin D, PTH, and calcium
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CHAPTER 1
1.0
BACKGROUND AND RATIONALE
1.1
INTRODUCTION
Hematopoietic cell transplant (HCT) is a potent immunotherapeutic treatment for children with high-risk
hematologic malignancies The 3 year overall survival of patients less than 21 years of age who
undergo an allogeneic HCT for acute leukemia in first clinical remission is 40-70%.2, 3 However,
survivors of childhood HCT are at lifelong risk for transplant-related late effects that can significantly
contribute to long-term impairment and mortality. The Bone Marrow Transplant Survivor Study reported
that adult patients who survived at least 2 years from allogeneic transplant were at 9.9-fold-increased
risk of death compared to the general population.4 Even 15 years from transplant, the mortality rates of
HCT patients remained higher than those of the general population and approximately 25% of these
deaths were attributed to late transplant-related toxicities.
In recognition of the growing number of HCT survivors, the importance of post-HCT long-term health,
and the absence of data regarding late effects in children, the National Cancer Institute and the
National Heart, Lung, and Blood Institute sponsored the First International Consensus Conference on
Late Effects after Pediatric HCT in April 2011.5 The conference brought together experts in the area of
pediatric HCT late effects and resulted in 7 summary articles that outlined key research needs calling
for multi-center studies.6-11 In response to the mandate the Pediatric Blood and Marrow Transplant
Consortium (PBMTC) formed the Late Effects Strategy Group. This multi-center proposal from the
PBMTC Late Effects Strategy Group is a comprehensive study of the late toxicities of pediatric HCT for
hematologic malignancy and is in direct response to the research priorities outlined at the consensus
conference.
This proposal seeks to prospectively collect comprehensive information about HCT late effects with
particular emphasis on renal, cardio-metabolic, and skeletal toxicities. We will collect comprehensive
data regarding late effects and establish a biologic sample repository from a large cohort of survivors of
childhood HCT. Second, we will prospectively study screening modalities to establish the incidence of
renal, cardio-metabolic, and skeletal late effects. Finally, we will examine potential biomarkers for
prediction of these organ specific late toxicities.
The burden of late effects is disproportionately borne by children with highly resistant hematopoietic
malignancies who require intensive therapy and receive allogeneic HCT. These very aggressively
treated children are a model from which new knowledge about the late sequelae of each of the parts of
their therapy can be learned and biomarkers predicting children at high risk for late effects can be
discovered. The resulting wealth of critical data will be used as a foundation for late effects clinical
research and interventional studies for years to come.
The etiologies of renal, cardio-metabolic, and skeletal late effects are multifactorial. However, there is
good evidence to suggest that they all share a common pathophysiology. The current understanding is
that a primary insult such as intensive chemotherapy and/or total body irradiation (TBI) leads to
endothelial cell injury, systemic inflammation, fibrosis, and ultimately end organ damage (figure 1). The
severity of the damage is variable and depends on host factors in the transplanted individual, pre-HCT
therapies, the transplant conditioning regimen, delayed immune tolerance, and acute toxicities of HCT.8
Furthermore, damage in one of these organ systems can contribute to toxicity in the others. It is well
established that chronic kidney disease (CKD) is associated with skeletal pathology and can result in
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abnormalities in mineral metabolism which may contribute to bone disease.12, 13 Additionally, these
abnormalities may be associated with cardiovascular (CV) morbidity.12-14 Metabolic changes that lead to
altered body composition may contribute to decreased bone density, but also to insulin resistance that
can increase CV risk.15-17 Finally, increased mortality in patients with CKD and end-stage renal disease
(ESRD) is attributed largely to CV events.18 Thus the conditions chosen for this study are closely
interrelated supporting the rationale for examining them together in the context of this study.
Figure 1. Proposed mechanism of cellular damage and organ
response. From Nieder, et al. NCI-NHLBI/PBMTC First
International Consensus Conference on Late Effects After Pediatric
Hematopoietic Cell transplantation: Long-Term Organ Damage and
Dysfunction. Biol Blood Marrow Transpl.17: 1573-1584, 2011.
1.2 Post-Transplant Chronic Kidney Disease
CKD is a common complication in long-term survivors of HCT, occurring in 20-60% of adult transplant
recipients and as many as 62% of pediatric HCT survivors.19-22 HCT survivors with CKD can progress
to ESRD. Survivors of HCT who develop ESRD have decreased survival compared to other patients
with ESRD who did not did not undergo HCT.23 Factors that contribute to CKD and ESRD may begin
during the acute transplant period. It has been demonstrated that the presence of proteinuria, a marker
of nephropathy, at transplant day 100 increases the risk of nonrelapse mortality (NRM) by as great as
6-fold by one year following HCT.19
1.2.1 Albuminuria
Albuminuria, defined as a urine albumin to urine creatinine ratio (ACR) between 30 to 299 mg/g
creatinine, is considered to be a marker of endothelial dysfunction and/or inflammation. 24 It is
postulated that albuminuria reflects a systemic, generalized endothelial injury and is associated with
increased risk of non-relapse mortality NRM in the first transplant year. Albuminuria has been identified
as a risk factor for cardiovascular and noncardiovascular mortality in the general and other patient
populations.18, 25-28However, little is known about risk factors for CKD progression or why CKD and
proteinuria increase NRM in the HCT patient population.
The group from Seattle Children’s Hospital generated data on albuminuria from a cohort of 142
primarily adult patients following HCT. The prevalence of albuminuria was 37% at baseline and 64% by
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day 100 post-transplant. Overt proteinuria was seen in 4% of patients at baseline and in 15% of
patients by day 100 post-HCT. Among 46 patients who were evaluated at 1-year, 50% had albuminuria
and 4% had overt proteinuria. Albuminuria and proteinuria at day 100 were associated with an
increased risk of CKD and non-relapse (HR=12.8; 95% CI 2.7-60.6) and overall mortality (HR=7.7;
95%CI 2.4-24.7) respectively 1-year after transplant.29 In univariable analysis, overt proteinuria at day
100 was strongly associated with increased risk of NRM (HR=12.8; 95% CI 2.7-60.6) and overall
mortality (HR=7.7; 95% CI 2.4-25.7). In multivariate analyses, subjects with overt proteinuria at day 100
were at a 6-fold risk of NRM (HR=6.8; 95%CI 1.1-41.5) after adjustment for acute and chronic GVHD.
The percentage of people with overt proteinuria who died a non-relapse death was 47% compared to
12.5% of patients with an ACR <300 mg/g creatinine. Before interventions that decrease albuminuria
and proteinuria can be tested as potential prevention and treatment modalities for CKD in this patient
population, we first need to accurately determine the prevalence of CKD, determine its natural history,
quantify the outcome of patients with CKD beyond year 1, and identify risk factors for progression and
non-relapse mortality NRM.
1.2.2 Creatinine, GFR, and Cystatin C
The identification of the most appropriate manner to assess kidney injury after HCT is critical as
conditioning regimens, medication dosing and treatment decisions are often based on renal function
and due to the potential association with late morbidity and mortality. Serum creatinine does not
accurately measure kidney function in patients with mild renal insufficiency 30, 31 The serum creatinine
level and related estimating equations, routinely used to estimate kidney function, are dependent on
factors such as muscle mass and weight that may fluctuate in HCT patients.32, 33 Therefore creatinine
may not accurately reflect kidney function in patients prior to and following HCT. Other methods for
assessing renal function include nuclear medicine glomerular filtration rate (GFR) and creatinine
clearance measured with 24-hour urine collection. Serum cystatin C, a cysteine protease inhibitor that
is expressed by all nucleated cells and is freely filtered by the glomerulus, correlates well with
measured GFR. It has been shown to more accurately measure kidney function than does creatinine in
patients with cancer, diabetes, and following renal transplantation.31, 34-37 To date, only one prospective
study has been done in the HCT population to evaluate cystatin C as a measure of renal function and
the role of cystatin C in HCT patients needs to be explored more thoroughly in a prospective fashion.38
1.2.3 Renal Biomarker Assessment
To better understand the role of inflammation in the development of CKD, we intend to investigate a
candidate novel biomarker, elafin, a member of the serpin family of endogenous protease inhibitors,
that inhibits neutrophil elastase and proteinase-3 released from activated neutrophils.39 The primary
mechanisms of neutrophil mediated tissue injury are generation of reactive oxygen species and
secretion of serine proteases.40 Imbalanced activity of these proteases can lead to ongoing tissue
injury, inflammation and cellular proliferation.39 The imbalance can be a result of insufficient control by
inhibitors such as elafin and/or excessive activity due to increased numbers of neutrophils in inflamed
tissues.39
Dr. Hingorani and colleagues at Seattle Children’s Hospital have shown that elafin levels correlate with
increased urinary ACR, GFR at day 100 and 1-year following HCT, and NRM at 1-year (see Table 1). In
this same cohort of patients, urinary elafin was associated with development of proteinuria
(p<0.001). Mean urinary elafin levels were higher in patients who develop CKD (GFR<60 mL/min/1.73
m2) at 1-year post-transplant (p<0.001). In addition, increasing urinary elafin was associated with an
increased hazard of overall mortality (p=.006) (unpublished preliminary data). The studies in this
proposal will provide us with a comprehensive understanding of CKD following pediatric HCT. The
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results of this work will provide information needed to identify and to investigate potential treatments for
children with CKD before there is irreversible dysfunction.
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One-Year GFR
Cytokine
Elafin
GFR
Group
< 60
Mean Level
p-value
Mean Level
p-value
2735.46
0.001
1505
0.0009
≥ 60
1899.9
.
2354
.
Table 1. Urinary elafin levels and associations with day 100 and 1-year GFR
1.3 Cardio-metabolic Risk
Survivors of pediatric allogeneic HCT are at risk for late CV disease and are at 2.3-fold risk of CV-related
death compared with the general population.41, 42 In an analysis of 2574 patients who had survived at least
five years for from HCT, the Seattle group reported that mortality rates were 4 to 9-fold higher than the
expected population rate for at least 30 years after transplantation.43 CV-related deaths were 1.9 times
greater than expected in the general population. The Bone Marrow Transplant Survivor Study investigated
hypertension, diabetes, and cardiovascular events in 1089 patients who had survived two-years or greater
after HCT. After adjustment for age, sex, race, and BMI, allogeneic HCT survivors were twice as likely as
siblings to report hypertension and 3.6 times more likely to report diabetes compared to their siblings.
Additionally, survivors of allogeneic HCT were more likely to report hypertension when compared to those
who underwent autologous HCT.4, 44 They demonstrated that long-term survivors of HCT have an
increased presence of the core findings of metabolic syndrome compared with leukemia survivors who did
not undergo HCT, and to healthy controls.41 Multiple factors likely contribute to the development of CV
toxicity including genetic predisposition, pre-HCT therapy, transplant conditioning, graft-versus-host
disease, post-HCT medications, potential immune mediated factors, changes in body composition, and
post-HCT metabolic syndrome.
1.3.1 Metabolic Syndrome and Body Composition
Metabolic syndrome, a clinical syndrome of high triglyceride (TG) levels, central obesity, hypertension,
hyperglycemia, low high-density lipoprotein (HDL) and cholesterol levels places HCT survivors at risk for
insulin dependence and early CV death and has been reported in children following allogeneic HCT.45 The
incidence of post-HCT metabolic syndrome is greater in children following HCT compared to the general
population and ranges from 7.5% to 32% in single center reports and a multi-center prospective
assessment is needed to better understand the scope of this problem45, 46 Changes in body composition
associated with metabolic syndrome following transplant likely contribute to the development of CV disease
and associated toxicities such as diabetes. Long-term HCT survivors have been shown to have altered
body composition characterized by an increased percent fat mass and decreased lean body mass despite
having a normal body mass index (BMI).4, 41 This distribution of body fat is termed sarcopenic obesity and
predisposes survivors to loss of muscle mass, hyperglycemia, and insulin resistance.47 Insulin resistance
is associated with the development of CV-disease and metabolic syndrome in healthy individuals. This has
not been investigated in children following HCT, particularly in a longitudinal fashion starting for the time of
HCT.
Dr. K. Scott Baker’s group at the Fred Hutchinson Cancer Research Center recently completed a study of
the impact of insulin resistance and abnormal body composition on CV risk in survivors after HCT for
hematologic malignancies. This cross sectional study included 151 HCT survivors and 92 sibling controls.
Survivors and siblings had a mean current age of 24 yrs, and survivors had undergone HCT at a mean age
of 11.2 yrs and were 13.5 years post-HCT (range 2.6 -31.5 yrs). Most patients (77%) received TBI with
HCT conditioning, 20% of those also cranial radiation (CRT) prior to or concurrent with TBI. The
remaining 23% received chemotherapy only. Two or more metabolic syndrome conditions were present in
63% of survivors who received TBI+CRT, 33% who received TBI only 23% who received chemotherapy
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only and 12% of sibling controls (P<0.001). Elevated levels of HDL, triglycerides, glucose, and waist
circumference were the most common conditions present in survivors. Individual risk factors for CV
disease in relation to HCT treatment exposures were also examined. Data were adjusted for age, sex and
Tanner stage and analyses were also performed with and without adjustment for obesity (percent fat mass,
PFM); effect size compared to sibling controls is shown in figure 2.
Figure 2. HDL cholesterol was significantly elevated in all HCT survivors regardless of HCT conditioning. Triglycerides were most
significantly elevated in survivors exposed to TBI+CNS XRT or TBI alone. Fasting blood glucose and insulin levels were used to calculate the
HOMA index, a surrogate marker of insulin resistance which is associated with CV risk. HCT survivors who received TBI all had significantly
elevated HOMA index compared to sibling controls. Black data markers indicate estimates adjusted for PFM HCT survivors did not have an
increase in their waist circumference; they had a significantly increased percent of fat mass, and a marked reduction in lean muscle mass.
Taken together these data demonstrate that by early adulthood, survivors of HCT during childhood already
have metabolic changes indicative of increased CV risk and that there are significant changes in body
composition that have occurred that likely contribute to the development of these risk factors. These data
do however leave us with gaps in our knowledge as due to the cross sectional nature of this study, we
cannot determine when these abnormalities begin to develop (i.e., early post-HCT or several years later)
and what other early post-HCT risk factors besides the HCT conditioning regimen might be contributing to
their development. The study thus proposed in this application will fill in those gaps and provide critical
data that will be needed in order to inform the development of interventions aimed altering the development
of these abnormal metabolic alterations.
1.3.2 Blood Pressure Monitoring
Effective blood pressure control has been shown over many years to decrease cardiovascular (CV)
morbidity and mortality in the general population.48 Multiple factors contribute to hypertension following
HCT including the effects of chemotherapy and radiation, graft-versus-host disease, post-HCT medications
such as corticosteroid and cyclosporine, and the patient’s underlying disease. The impact of hypertension
in the acute post-HCT period on late morbidity and mortality has not been prospectively investigated in a
large pediatric population. A more detailed understanding of the course, risk factors for and implications of
post-HCT hypertension is needed.
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The assessment of a patient’s blood pressure may be performed using in-office or causal blood pressure
(cBP) measurement, home blood pressure monitoring or ambulatory blood pressure monitoring (ABPM)
over 24hours.48 Blood pressure assessment is most commonly made based on causal blood pressure
(cBP) measurements.49 Recognized shortcomings of cBP assessment are that blood pressure is variable
over 24 hours and that it can be affected by the office environment (white-coat hypertension).50-52
Ambulatory blood pressure monitoring (ABPM), a technique in which multiple BP measurements are
obtained using an automatic device over a prolonged period, offers advantages that can overcome the
shortcomings of cBP measurements.6,53,12-14 With ABPM, blood pressure is measured in the patient’s usual
environment, eliminating the white coat effect and allowing assessment of circadian variability. ABPM has
been shown to be superior to cBP for detecting the elevated CV risk associated with conditions such as
obesity and diabetes and is considered standard care for the evaluation of pediatric hypertension.6,13,54
There is no data in the HCT population regarding ABPM despite the fact that many children develop
hypertension post-transplant.
This study prospectively assesses the change in blood pressure and the impact of that change in the two
years following HCT. All patients will have prospective cBP monitoring as this is readily available at all
centers. 24-hour ABPM is not available at all centers and will be performed at a subset of centers as an
exploratory aim.
1.4 Skeletal Late Effects
HCT may result in decreased bone mineral density, which may lead to osteopenia and osteoporosis with
associated increased risk of fracture, loss of independence, immobility, chronic pain, and an overall
decreased quality of life. The Bone Marrow Transplant Survivor Study reported a prevalence of
osteoporosis of 9% in long term survivors (median age 36.5 years) of HCT for acute leukemia.55 This was
significantly higher than the prevalence of 2.2% in the siblings of the transplant patients. Allogeneic
transplant and female sex was associated with increased risk of osteoporosis. There are few reports of
post-transplant BMD changes in children and most are from small, single center, and retrospective
studies.56-59 The single prospective analysis of 29 children following HCT demonstrated that most bone
mineral loss occurs within the first six months following transplant.57 Studies of adult HCT patients
demonstrate that post-transplant bone turnover is characterized by increased resorption and decreased
bone formation and that alteration in BMD is preceded by changes in markers of bone turnover such as
serum osteocalcin, serum alkaline phosphatase, and urine N-telopeptide. It is not known if these patterns
are the same in children and a detailed understanding of how bone mineral status changes during and after
HCT is lacking.
Children are at risk for decreased BMD following HCT due to factors related to their diagnosis and
treatment including the underlying disease, pre-HCT therapy (especially with steroids), conditioning
chemotherapy and TBI, osteotoxic medications, and presence of and treatment for GVHD. 9 Studies of
adult patients have shown that the chemotherapy and radiation used in HCT conditioning can mediate
skeletal toxicity in two ways. First, damage can occur through direct insult to osteoprogenitor cells.60-62
Secondly, cytokine release during the initial weeks after HCT can activate osteoclasts resulting in
increased bone resorption.63, 64 The RANK/RANKL/OPG pathway is thought to be the primary mediator of
osteoclastic resorption following conditioning.62, 65 Receptor activator of the nuclear factor- κB ligand
(RANKL) and RANKL/OPG (osteoprotegerin) ratio increase after transplant stimulating
osteoclastogenesis.62, 65
1.4.1 Vitamin D Deficiency
Additional risk factors are related to transplant-related convalescence and complications including lack of
activity, nutritional compromise, endocrine deficiencies, and calcium and vitamin D deficiency. 25-OH
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vitamin D deficiency is a known risk factor for skeletal toxicity which may precipitate or exacerbate
osteopenia and osteoporosis.66 Results from a prospective study of 25-hydroxy (OH) vitamin D deficiency
in a cohort of 67 pediatric patients in the first year following transplant during three seasons in New
England demonstrated levels in the insufficient (20-30 ng/mL) or deficient (<20 ng/mL) range in 80.6% of
subjects.67 The mean 25-OH vitamin D level was 22.8 ng/mL (institutional normal > 30 ng/mL). In
multivariate analysis, only older age at the time of transplant was found to be a risk factor for vitamin D
deficiency. Patients with deficient levels were prescribed 6 weeks of ergocalciferol repletion. The mean
change in 25-OH vitamin D levels following supplementation was 18.8 (SD = 11.3, range: 8-42). Of the
evaluable subjects, 63.6% had a post-supplementation level in the normal range, 31.8% had levels in the
insufficient range, and 4.5% remained deficient. Unexpectedly, there was no correlation between 25-OH
vitamin D and parathyroid hormone (PTH) levels.
Pretransplant factors likely impact vitamin D levels and skeletal health in HCT survivors and in a separate
cohort of 104 patients assessed prior to the start of HCT conditioning, the same group identified 25-OH
vitamin D insufficiency and/or deficiency in 71% (median level 26.4 ng/mL, range 7.6-104 ng/mL) of
children
1.4.2 Dual-Energy Absorptiometry (DXA)
DXA is a non-invasive technique that was originally designed to measure bone mass and mineral content.
However, whole body DXA can be used to assess body composition by measuring the content of both the
bone mineral and soft-tissues. Whole body DXA divides the body into bone, fat-free and bone-free tissue,
and fat and operates on the principle that photon attenuation in vivo is a function of tissue composition.68-70
The body is divided into a series of pixels, the photon attenuation of the pixels is measured at two energies,
and a ratio of attenuation calculated at each of the two energies.70 Body components, bone-mineral, fat,
and lean soft tissue can be distinguished by the ratios of the two energies. DXA that has been validated in
children and is commonly used in studies of osteoporosis and body composition.71, 72, 73 Pre- and Post-HCT
DXA screening is routinely performed at many pediatric transplant centers, but has not been studied
prospectively. This investigation will use DXA to assess changes in BMD, lean body mass, and total
percent fat mass in children following transplant.
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CHAPTER 2
2.0
STUDY DESIGN
2.1
STUDY OVERVIEW
This is a prospective non-therapeutic study, assessing the long-term toxicity of HCT for childhood
leukemia. This study is collaboration between the Pediatric Blood and Marrow Transplant Consortium
(PBMTC), the Center for International Blood and Marrow Transplant Research (CIBMTR), the National
Marrow Transplant Program (NMDP) and the Resource for Clinical Investigation in Blood and Marrow
Transplantation (RCI-BMT) of the CIBMTR. The study employs standardized post-HCT screening
methods to establish the cumulative incidence of CKD, metabolic syndrome, and osteopenia and
assesses potential biomarkers associated with late effects while examining the hypotheses that
survivors of pediatric HCT are at risk for late organ toxicity and they will have identifiable biomarkers
present within the first two years following HCT which will be predictive for late adverse outcomes
allowing for early identification of patients at risk.
2.2
HYPOTHESES AND STUDY OBJECTIVES
2.2.1. Hypotheses
1. Elevated urinary albumin and protein to creatinine ratios prior to and following HCT will be
predictive for the development of CKD at 1-year following transplant.
2. Systemic hypertension as measured with intermittent blood pressure assessment at day +100 will
be associated with albuminuria, proteinuria, and the development of CKD at 1 and 2-years following
HCT.
3. Serum cystatin C levels will provide accurate measurement of renal function compared to nuclear
medicine GFR, 24-hour creatinine clearance, and estimating equations of creatinine clearance prior
to the start of the conditioning regimen and at 1 and 2-years following HCT.
4. The presence of increased levels of the protein biomarker elafin in the urine will be associated with
the development of CKD at 1 and 2-years following HCT.
5. Markers of metabolic syndrome, including elevated TG, increased LDL, reduced HDL, and elevated
fasting glucose will be present at day (+) 100, and remain abnormal at 1 and 2- years following
HCT.
6. Compared to pre-HCT measurements, changes in body composition (increased percent fat mass
and decreased lean body mass) as assessed by DXA will be evident at and will be correlated with
adverse metabolic syndrome markers at one and two years following HCT.
7. The risk for metabolic syndrome and abnormal body composition at 1 and 2-years post-HCT will be
associated with exposure to TBI as part of the conditioning regimen.
8. Compared to pre-HCT values, mean total body BMD will be significantly decreased at 1 and 2years following transplant.
9. Biomarkers of bone turnover, including decreased levels of osteocalcin and bone specific alkaline
phosphatase and increased levels of urinary N-telopeptide at day (+) 100 will be predictive of loss of
BMD at 1-year
10. The presence of kidney dysfunction at day (+) 100 will be associated with BMD loss at 1-year postHCT
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11. Plasma and DNA collected prospectively at scheduled intervals after HCT will develop a critical
resource for the study of late effects in the future including genetic risk factors and additional or new
biomarkers.
2.2.2 Objectives
Primary Objective
To report the incidence of CKD, metabolic syndrome, and osteopenia at 1 and 2-years following
allogeneic HCT for hematologic malignancy
Secondary Objectives
1. To identify prognostic risk factors for the development and progression of post-HCT CKD, metabolic
syndrome, and osteopenia at 1 and 2-years following HCT
2. To investigate potential associations of systemic hypertension as measured with intermittent blood
pressure assessment with proteinuria, AKI, and CKD at day 100 and at 1 and 2-years following
HCT
3. To compare the results of GFR estimating equations based on serum cystatin C levels or serum
creatinine to GFR measured by nuclear medicine GFR and/or 24-hour creatinine clearance prior to
and at 180 days and 1 and 2-years following HCT
4. To explore potential association of the protein biomarker elafin in the urine at with the development
of CKD at 180 days and1-year and 2-years post-HCT
5. To report levels of fasting TG, LDL, HDL, insulin, and glucose prior to HCT at days 100, 1-year, and
2-years following HCT
6. To assess change in body composition including BMD, BMI, percent fat mass and lean body mass
as measured by DXA at 1-year and 2-years post-HCT compared to pre-HCT values.
7. To assess the presence of osteopenia by x-ray in patients unable to undergo DXA without sedation.
8. To report levels of markers of bone turnover including serum osteocalcin, bone specific alkaline
phosphatase, and urine N-telopeptide prior to HCT at days 30, 100, 1-year, and 2-years following
HCT
9. To develop a repository for plasma and DNA to be used in future investigation of HCT-associated
late effects
2.3
Eligibility Criteria
Inclusion Criteria
1. Age less than 22 years at admission for HCT. There is no lower limit on age.
2. Planned allogeneic HCT from any donor and stem cell source. There are no study-specific criteria
for HLA-matching.
3. Disease and disease status criteria
a. Acute lymphoblastic leukemia/lymphoma in complete morphologic remission defined as a M1
marrow (<5% blasts) with no evidence of active extramedullary disease within 30 days of the
start of the conditioning regimen; OR
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b. Myelodysplasia (regardless of subtype) with less than 10% marrow blasts within 30 days of the
start of the conditioning regimen; OR
c. Acute myelogenous leukemia in complete morphologic remission defined as a M1 marrow (<5%
blasts) with no evidence of extramedullary disease within 30 days of the start of the conditioning
regimen; OR
d. Juvenile myelomonocytic leukemia; OR
e. Chronic myelogenous leukemia excluding refractory blast crisis.
4. Planned myeloablative conditioning regimen, defined as a regimen including one of the following as
a backbone agent:
a. Busulfan ≥ 12.8 mg/kg total dose (IV or PO). PK-based dosing allowed, if the intent is total
overall dose ≥ 12.8 mg/kg; OR
b. Total Body Irradiation ≥ 1200 cGy fractionated; OR
c. Treosulfan ≥ 30 g/m2 total dose IV
Regimens may include other agents as long as at least one of the above criterion is met.
5. Enrollment in the following NMDP research protocols:
a. Protocol for a Research Database for Hematopoietic Cell Transplantation, Other Cellular
Therapies and Marrow Toxicity Injuries
b. Protocol for a Research Sample Repository for Allogeneic Hematopoietic Stem Cell
Transplantation and Marrow Toxic Injuries
A subject must provide consent to both of these NMDP research protocols to be eligible for
participation in the 13-TLEC study.
6. Written informed consent document signed by patient if the age is greater than or equal to 18 years
and the patient is developmentally able to provide consent. The informed consent document is to
be signed by the parent or legal guardian if the patient’s age is less than 18 years or if the patient is
greater than or equal to18 years, but developmentally unable to provide consent. Assent will be
obtained according to the guidelines of the patient’s transplant institution.
Exclusion Criteria
1. Prior allogeneic or autologous HCT
2. Patients with renal disease prior to the start of HCT conditioning requiring the use of dialysis at the
time of enrollment and/or GFR < 60 mL/min/1.73 m2
3. Patients with osteopenia or osteoporosis treated with a bisphosphonate medication at any time prior
to enrollment
4. Patients with preexisting diabetes or hyperglycemia treated with insulin or oral hypoglycemic
medication at the time of enrollment
5. Patients with uncontrolled viral, bacterial, fungal or protozoal infection at the time of study
enrollment
6. Karnofsky performance score or Lansky Play-Performance Scale Score < 60 at the time of study
enrollment
7. Known inherited or constitutional predisposition to cancer including Down Syndrome, Li-Fraumeni
syndrome, Fanconi Anemia, and patients with BRCA1 and BRCA2 mutations
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2.4
STUDY PROCEDURES
2.4.1 Consent and Protocol Co-Requirements
Informed consent is to be obtained within 60 days of the start of the transplant conditioning regimen. No
study screening tests or procedures are to be performed until after written consent, and assent when
appropriate, is obtained.
All centers opening this protocol will also be required to participate in the following NMDP research
protocols: Protocol for a Research Database for Hematopoietic Cell Transplantation, Other Cellular
Therapies and Marrow Toxicity Injuries and Protocol for a Research Sample Repository for Allogeneic
Hematopoietic Stem Cell Transplantation and Marrow Toxic Injuries. This protocol requires that all
enrolled recipients must be enrolled on these NMDP research protocols and consent to providing
baseline pre-conditioning blood samples to the NMDP Repository. Therefore, centers opening this
study will need to have current IRB approvals for NMDP protocol recipient consents in order to submit
samples in the context of both related donor and unrelated donor HCTs.
2.4.2 Data Collection
Data regarding pre-HCT morbidity, potential risk factors, and the presence of late effects will be
collected longitudinally through both CIBMTR research level forms or in study-specific data collection
forms.
2.4.2.1 Pre-HCT Data
Baseline assessment includes patient related variables, disease status at the start of HCT
conditioning, preexisting morbidity, prior cancer directed therapy, organ function present prior to
the start of HCT conditioning, prior corticosteroid use, and medications used to treat hypertension,
diabetes/hyperglycemia, lipid abnormalities, osteopenia/osteoporosis, and renal insufficiency at
enrollment.
Patient related variables

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Age at start of HCT conditioning
Gender
Lansky Play Performance Score (patients less than 16 years)/Karnofsky Performance Score
(patients aged 16 years or greater) at the start of HCT conditioning Height and weight at the
start of HCT conditioning
Cigarette smoking at any time prior to and within one year of the start of conditioning and
actively at the start of conditioning; number of years of cigarette smoking
Disease and pre-HCT related variables

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Primary disease for which HCT was performed
Disease status and number of complete remission at start of the HCT conditioning
History of malignant disease other than the primary disease for which the HCT was performed
Cranial radiation and total dose prior to start of the HCT conditioning regimen
Chest radiation and total dose prior to the start of the HCT conditioning regimen when
applicable
Total cumulative anthracycline chemotherapy (reported as doxorubicin equivalents) prior to
the start of the HCT conditioning regimen; Doses should be given in doxorubicin equivalents
using the following calculations.
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Calculations for isotoxic doxorubicin equivalents
Cumulative dose of doxorubicin (mg/m2) x 1 =
mg/m2 = doxorubicin equivalent dose
Cumulative dose of daunorubicin (mg/m2) x 0.833 =
dose
Cumulative dose of idarubicin (mg/m2) x 5 =
mg/m2 = doxorubicin equivalent
mg/m2 = doxorubicin equivalent dose
Cumulative dose of mitoxantrone (mg/m2) x 4 =
mg/m2 = doxorubicin equivalent dose
Significant coexisting diseases or organ impairment at any time prior to the preparative
regimen
History of any of the following prior to or at the start of the HCT conditioning regimen:

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
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
Congestive heart failure (EF <50%)
Coronary artery disease without prior myocardial Hypertension
Myocardial infarction Congenital heart disease
Constitutional chromosomal abnormality
Stroke and/or cerebrovascular accident
Diabetes mellitus
Thyroid disease
Renal failure requiring dialysis
Acute or chronic kidney disease requiring medical treatment Dyslipidemia (triglyceride level
> 150 mg/dL, HDL cholesterol level < 40 mg/dL and/or LDL cholesterol level > 130 mg/dL)
Osteopenia and/or osteoporosis with history of fracture Avascular necrosis
Medication use prior to and at the start of the conditioning regimen
Use of any of the following medications or supplements within 30 days of the start of the
conditioning regimen:

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

Insulin
Oral hypoglycemic agents
Antihypertensive medications
Medications to treat dyslipidemia
Ergocalciferol or cholecalciferol
Supplemental calcium
Systemic corticosteroid
2.4.2.2 Transplant Specific Data

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Conditioning regimen used, including field and total dose of radiation
Total doses of drugs used as part of the conditioning regimen
Product type (bone marrow, peripheral blood stem cells, umbilical cord blood, multiple cord
bloods, other)
Donor type (syngeneic twin, HLA-identical sibling, HLA-matched other relative, unrelated donor)
Degree of HLA mismatch
Date of stem cell infusion GVHD prevention regimen used: T-cell depletion, calcineurin
inhibitor/methotrexate, calcineurin inhibitor/methotrexate/corticosteroid, calcineurin
inhibitor/mycophenolate mofetil
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2.4.2.3 Post-HCT Data
The following post-HCT data will be collected from CIBMTR forms or study-specific forms at 100
days +/- 14 days, 180 days +/- 21 days, one year +/- 30 days, and two years +/- 60 days following
transplant:



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



Receipt of donor cellular infusion or subsequent transplant following the initial transplant
Acute GVHD
o Development of acute GHVD including organ system involvement Maximum overall
grade of acute GVHD
Therapy used to treat acute GVHD
Chronic GVHD
o Development of chronic GVHD including organ system involvement
o Maximum grade and severity
o Therapy used to treat chronic GVHD
The development of any of the following since the start of the conditioning regimen
o Acute kidney injury and/or chronic kidney disease, treatment with dialysis or
hemofiltration, and/or other renal directed therapy including medications
o Dyslipidemia (diagnosed when not receiving parenteral nutrition) requiring medical
treatment
o Hypertension requiring treatment with medication
o Congestive heart failure
o Myocardial infarction
o Stroke/seizure
o Diabetes/hyperglycemia requiring the use of insulin and/or oral hypoglycemic medication
o Gonadal dysfunction and gonadal hormone replacement therapy Growth hormone
deficiency and growth hormone replacement therapy Hypothyroidism and thyroid
replacement therapy Skeletal fracture including site
Osteopenia and/or osteoporosis
Lansky or Karnofsky performance score
Use of any of the following medications or supplements during the preceding study interval,
including the name of the medication(s) and start and stop dates given as month and year
(when available):
Calcineurin inhibitors
Rapamycin
Insulin
Oral hypoglycemic agents
Antihypertensive medications
Medications to treat dyslipidemia
Ergocalciferol or cholecalciferol
Supplemental calcium
Bisphosphonates
Total cumulative dose of corticosteroid for GVHD prophylaxis or treatment since last
reporting period. Patients who receive corticosteroid will havean assessment every two
months until discontinuation of the medication. Assessment will resume if patient restarts
corticosteroid at any time until the completion of the study.
Treatment with any of the following therapeutic interventions during the preceding study interval:
o Renal dialysis
o Kidney transplant
o Surgical intervention for osteopenia/osteoporosis or associated-complications including
fracture
21 o
o
o
o
o
o
o
o
o
o
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
Survival status (alive without relapse, alive with relapse, dead)
Main cause of death when applicable
o Relapse/progression/persistent disease
o HCT related causes and specific cause of death including GVHD, cardiac toxicity,
infection, pulmonary toxicity, rejection/poor graft function, VOD, other
o New malignancy
o Other or unknown
2.4.3 Nuclear Medicine GFR, Creatinine Clearance, and Cystatin C
An estimated GFR (eGFR) will be calculated by the study team with values provided by the transplant
center for all patients prior to transplant and at the time points listed in section 4.2. Estimating equations
of GFR will be calculated using two formulas: the Schwarz formula, which is a creatinine based formula
and an age-based formula based on cystatin C.
Additionally, the GFR will be measured with either nuclear medicine GFR or 24-hour creatinine
clearance at the subject’s treating center according to the institutional standard for renal assessment
prior to transplant. A nuclear medicine GFR preferred, but not required. Nuclear medicine GFR or 24hour creatinine clearance will be performed at the intervals outlined in section 4.2. The same method
must be used at each time point.
Nuclear medicine GFR, eGFR, and 24-hour creatinine clearance are to be reported in mL/min/1.73 m2.
The creatinine clearance estimation using the Schwartz formula.74
Estimated GFR using Schwarz formula
eGFR =
K x height (cm)
Serum Creatinine (mg/dL)
Where K is 0.413
The creatinine clearance estimation using Cystatin C based formulas.
Pediatric formula for patients ≤ 17 years
eGFR = 39.1 x (height/SCr)0.516 x (1.8/CysC)0.294 x (30/BUN)0.169 x (1.099)male x (height/1.4)0.188
The Inker-CKD-EPI formula for patients ≥ 18 years 75
eGFR = 135 × min (Scr/κ, 1) α × max (Scr/κ, 1) − 0.601 × min (Scys/0.8, 1) − 0.375 × max
(Scys/0.8, 1) − 0.711 × 0.995 Age [× 0.969 if female] [× 1.08 if black]
Scr = serum creatinine
Scys = serum cystatin C
K is 0.7 for females and 0.9 for males
α is −0.248 for females and −0.207 for males
Min indicates the minimum of Scr/ K or 1
Max indicates the maximum of Scr/ K or 1
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Urinalysis and Serum Creatinine
Serum creatinine and urinalysis for albumin and protein will be performed at the patient’s transplant
center with the results reported centrally. Urine protein (mg/dL), albumin (g/g), and creatinine (mg/dL)
will be performed at the intervals outlined in section 4.2. This can be done on a spot urine sample,
preferably a morning sample. Serum creatinine (mg/dL) will be measured at the same intervals.
Urine elafin collection and shipment
Urine for elafin will be collected at the intervals outlined in section 4.2. A total of 8-10 cc of urine for
elafin will be aliquoted in 2 mL tubes and either placed on dry ice and shipped overnight or frozen at 80 Celsius until analysis.
Attn: Name (Emily Pao)
Fred Hutchinson Cancer Research Center
1100 Fairview Ave N. D2-281
Seattle, WA 98109
The results of urine elafin testing for individual patients will not be reported back to transplant centers
and cannot be used for clinical purposes. Results will be reported centrally using the subject’s
research identification number.
2.4.4 Blood Pressure Measurement
24-hour blood pressure monitoring will be performed in a subset of patients at Seattle Children’s
Hospital as an exploratory aim. Hypertension is defined as a systolic blood pressure and/or diastolic
blood pressure greater than or equal to the 95th percentile for sex, age, and height on two or more
occasions. A table of normal blood pressure values for children and adolescents is found in Appendix
A.
2.4.5 Body Composition Measurement
DXA will be used to measure percent fat mass, lean body mass and total body BMD. DXA will only be
performed when the patient is able to participate without need for sedation and in children without
increased radiation sensitivity. Those who are unable to perform DXA scanning are eligible for
participation in the rest of the study. DXA will be performed at the intervals outlined in section 4.2
BMD measurements of the whole body, hip and spine will be reported as Z-score. Whole body
scanning is required for body composition analysis and is required. Hip and spine measurements are
not required, but the results will be recorded when performed. Sex and age specific Z-scores will be
calculated using normative values defined for the scanner used at the subject’s transplant center. It is
strongly recommended, though not required that the DXA assessment is performed on the same
scanner at each time interval tested.
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Children who are unable to perform DXA without sedation will have a chest radiograph performed to
assess for increased radiolucency. Effort should be made for the radiography to be performed when
one is required for clinical purposes if possible.
Whole body fat percentage will be calculated as total-body fat mass (kg)/total body mass (kg) x100
with data provided by DXA. High fat mass (adiposity) is defined as body fat percent (BF%) >
McCarthy's 85th percentile of body fat reference data (Appendix E).76 Lean body mass in grams will be
obtained from DXA-measured body-composition data.
Body mass index (BMI) will be reported as kg/m2 and calculated as the mass (kg)/ height (cm). Height
and weight will be obtained by using standard procedures. Subjects with a BMI 85-95% for age and
sex will be classified as overweight and those with a BMI greater than or equal to 95% will be defined
as obese. Sex-specific BMI percentiles will be determined using the 2000 CDC reference data and
growth charts (Appendix B).77 BMI will be assessed at the time intervals outlined in section 4.2.
Waist circumference will be reported in centimeters and assessed with tape measure placed at the
level of the umbilicus
2.4.6 Metabolic Marker Laboratory Testing
Levels of TG (mg/dL), HDL (mmol/L or mg/dL), LDL (mmol/L or mg/dL), insulin (pmol/L), and glucose
(mg/dL) will be measured at the treating center according to institutional standards for fasting
according to the schedule of required data and studies in section 4.2.
2.4.7 Markers of Bone Metabolism, 25-OH Vitamin D, N-Telopeptide and Parathyroid Hormone
Levels of serum osteocalcin (nmol/L or g/L), bone specific alkaline phosphatase (g/L), parathyroid
hormone (pg/mL or pmol/L), calcium (mg/dL), 25-OH vitamin D (ng/mL or nmol/L), and urinary Ntelopeptide (nmol bone collagen equivalents/mmol creatinine) will be measured at the treating institute
according to institutional standards according to the schedule of required data and studies in section
4.2.
2.4.8 Biorepository Sample Collection and Shipment
Patients will have peripheral blood samples collected prior to the start of conditioning and at scheduled
intervals (see section 4.2 for table of required data). Collected samples will be processed at the local
center and periodically batch-shipped to the CIBMTR for storage in the sample biorepository.
2.4.8.1 Biorepository Collection
Blood will be drawn for the biorepository at the time pointes listed in section 4.2. A minimum of 710 cc will be collected in an EDTA tube at the time points specified.
Biorepository patient samples can be collected and processed locally Monday-Sunday of any
given week. Samples will be periodically batch-shipped to the CIBMTR Research Repository for
long-term storage. Sample monitorint will be performed by RCI-BMT. Samples will be shipped to:
CIBMTR Research Repository
711 5th Street SW, Suite 6
New Brighton, MN 55112
An additional sample for DNA will be drawn prior to transplant under the NMDP Repository
Sample Protocol consent (13-TLEC protocol co-requirement) and at no other time points. 17 mL
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of whole blood is to be collected into two 8.5 mL-fill ACD tubes. Details of sample collection,
labeling and blood tube shipment instructions are provided in the Critical Facts Sheet associated
with the NMDP Research Sample Protocol.
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CHAPTER 3
3.0
STUDY ENDPOINTS
3.1
PRIMARY ENDPOINT: CHRONIC KIDNEY DISEASE, METABOLIC SYNDROME, AND
OSTEOPENIA AT ONE AND TWOYEARS POST HCT
3.1.1
Chronic kidney disease is defined as meeting one of the following:
1. Kidney damage for >= 3 months, as defined by structural or functional abnormalities of the
kidney marked by pathological abnormalities (if performed for clinical care, not required by
study protocol) or markers of kidney damage, including abnormalities in the composition of
the blood or urine (such as, elevated serum creatinine or cystatin C and/or proteinuria or
albuminuria) and, or abnormalities in imaging testing (if performed for clinical care, not
required by study protocol). Decreased GFR may or may not be present.
2. GFR < 60 mL/min/1.73 m2 for >= 3 months with or without kidney damage as defined above.
3.1.2
Metabolic syndrome is defined based on the Adapted-NCEP definition.78,79
Patients must have >= 3 of the following:
1. Abdominal obesity: defined as a waist circumference >= 75 percentile for age and gender
(see appendix D)
2. High triglyceride level: >= 90th percentile for age and gender (see appendix C)
3. Low HDL-cholesterol level: < 1.03 mmol/l or 40 mg/dL
4. Elevated blood pressure: Systolic or diastolic blood pressure >= 90 percentile based on
reference values for North American children and adolescents (see appendix A)
5. Fasting hyperglycemia: >= 6.1 mmol/l or 110 mg/dL
3.1.3
3.2
Osteopenia is defined as a Z-score between -1.0 and -2.0 in any area assessed by DXA or
increased radiolucency reported by an attending radiologist on radiograph, computed
tomography, or magnetic resonance imaging.
SECONDARY ENDPOINTS
3.2.1
Hypertension: Systolic or diastolic blood pressure >= 90 percentile based on reference values
for North American children and adolescents (see appendix A)
3.2.2
Acute kidney injury is defined as any of the following:80

Increase in SCr by x 0.3 mg/dL (x26.5 lmol/L) within 48 hours; OR

Increase in SCr to1.5 times baseline, which is known or presumed to have occurred within
the prior 7 days; OR
Urine volume <0.5 mL/kg/h for 6 hours.

3.2.3
Dyslipidemia defined as triglycerides >150 mg/dL, LDL cholesterol >130 mg/dL or HDL
cholesterol <40 mg/dL, and/or the use of lipid lowering medications.
3.2.4
Osteoporosis: Z-score less than -2.0 in any area assessed by DXA and/or non-traumatic
fracture.
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3.3
3.2.5
Albuminuria is defined as a urine albumin to urine creatinine ratio (ACR) between 30 to 299
mg/g creatinine in a spot urine sample.
3.2.6
Proteinuria is defined as the presence of protein > 300 mg/g creatinine in a spot urine sample.
3.2.7
Adiposity is defined as body fat percent (BF%) > McCarthy's 85th percentile of body fat
reference data (Appendix E).
3.2.8
Obesity is defined as a BMI >= 95% for age and sex using the 2000 CDC reference data and
growth charts (Appendix B).
3.2.9
Vitamin D deficiency is defined as a 25-OH vitamin level less than 20 ng/mL (50 nmol/L).
TERTIARY ENDPOINTS
3.3.1 BMD reported as the whole body Z-score from DXA.
3.3.2 BMI calculated as outlined in section 2.4.5 and reported in percentile normalized for age and
sex (see Appendix B)..
3.3.3 GFR defined as the value reported in mL/min/ 1.73 m2 measured by nuclear medicine GFR or
24 hour creatinine clearance
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CHAPTER 4
4.0 PATIENT REGISTRATION AND ENROLLMENT
4.1 PATIENT REGISTRATION AND ENROLLMENT
Patients having documented consent and meeting all eligibility criteria for the study will be registered
using the CIBMTR Forms Net internet data entry system.
The following procedures should be followed:
1. The13-TLEC Enrollment Form is completed in the data management system. The patient must be
successfully enrolled prior to collection of the any data or performance or protocol specific
diagnostic study.
2. After the patient is enrolled and the transplant date confirmed, the center completes FormsNet
Form 2400 Pre-Transplant Essential Data (Pre-TED).
3. After the CRID number is obtained by completing Form 2804, the center completes the studyspecific Transplant Form to confirm the patient’s CRID and the actual date of transplant.
4. After Transplant, the patient’s follow-up data will be collected using the Research Level Forms in
the CIBMTR Forms Net internet data entry system.
The following forms will be collected:

Form 2000 – Recipient Baseline Data

Form 2005 – Confirmation of HLA typing

Form 2100 – 100 Days Post-HCT Data

Form 2200 – Six Months to Two Years Post-HCT Data

Form 2900 – Recipient Death Data (if applicable)

Post-Transplant disease-specific forms

Form 2110 AML Post-HSCT Data

Form 2111 ALL Post-HSCT Data

Form 2112 CML Post-HSCT Data

Form 2114 Myelodysplasia/Myeloproliferative Disorders Post-HSCT Data

Form 2115 JMML Post-HSCT Data
5. Data not available from the CIBMTR forms listed above will be entered in the study specific
database.
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4.2 SCHEDULE OF REQUIRED DATA AND STUDIES
The following data and studies are required:
Recommended Standard of Care 
Pre-HCT
Baseline morbidity
Late effects assessment 81, 82
Noncorticosteroid medication
and therapeutic intervention
assessment
Corticosteroid assessment
Weight, height, and waist
circumference 81, 82
Blood pressure 81, 82
24-hour blood pressure ¶
Urine Protein & Albumin 81, 82
GFR or creatinine clearance
Calculated eGFR
Serum & urine creatinine 81, 82
Fasting TG, HDL, and LDL 82
Fasting insulin & glucose 81
DXA 81, 82 or chest
radiograph
Vitamin D, PTH & calcium 82
Day 30 +/7 days
Day 100 +/14 days
Day 180 +/21 days
1-year +/30 days
2-year +/60 days
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X*
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Research Related Studies
Repository plasma
GFR or creatinine clearance
Urine elafin
Osteocalcin, bone specific
alkaline phosphatase, urine
N-telopeptide
X
X
X
X
X
X
X
X
X
X
Pre-HCT assessment within 30 days of the start of the conditioning regimen
* Height not required at day 30 assessment; ¶ Only performed for subjects from Seattle Children’s Hospital. 
Corticosteroid dose to be assessed every two months until discontinued. Assessment will resume if
corticosteroid is restarted at any time until the completion of the study.
eGFR calculated using the Schwarz and Rule formulas.
References supporting the data/studies as standard of care are cited next to each item.
DXA is preferred. Chest radiograph is to be performed in children who are unable to undergo DXA without
sedation.
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4.3 DATA REPORTING
Criteria for forms submission
A detailed description of each of the forms and the procedures required for the forms completion and
submission timelines can be found in the Data Collection Instructions. Forms that are not entered into
the internet data entry system within the specified time will be considered delinquent. A missing form
will continue to be requested until either the form is entered in the data entry system, or until an
exception is granted.
4.4
ADVERSE EVENT REPORTING
This is a prospective, non-therapeutic study examining the natural history and risk factors of post-HCT
late effects and developing a biorepository for future studies. All therapy administered for the prevention
or treatment of late effects is at the discretion of the transplant program per institutional protocols and is
not considered investigational. Real-time monitoring of adverse events will not be done.
4.5
UNANTICIPATED PROBLEMS
Unanticipated problems include unexpected problems, events, or new information which are not
adverse events but which indicate that research participants or others are at greater risk of harm than
previously believed prior to recognition of the unanticipated problem. Pregnancy in a subject would also
be considered an unanticipated problem and should be reported as an unanticipated problem.
4.6
DATA SAFETY MONITORING
This study will be centrally reviewed and followed by the Data Safety and Monitoring Committee
(DSMC) of the Pediatric Blood and Marrow Transplant Consortium (PBMTC). The DSMC will review the
study protocol prior to study activation and IRB review, and will continue to review the study on a
regular basis according to the rules of the committee. If the DSMC recommends protocol or informed
consent changes during the study, then they will be distributed to participating centers. It is the
responsibility of the principal investigator at each institution to forward distributed communications from
the DSMC to their local IRB.
4.7
STUDY MONITORING
The participating principal investigator and institution will permit study-related monitoring visits by
representatives of the CIBMTR, PBMTC or designees to ensure proper conduct of the study and
compliance with all safety reporting requirements. Access will be provided to the facilities where the
study activities took place, to source documents, to CRFs, and to all other study documents.
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CHAPTER 5
5.0 STATISTICAL CONSIDERATIONS
5.1
STUDY DESIGN
This is a nonrandomized prospective cohort study of 340 patients undergoing HCT for treatment of
childhood leukemia and myelodysplasia. All subjects will have assessment of preexisting morbidity and
potential risk factors, collection of specimens for banking, scheduled late effects monitoring, laboratory
analysis, and screening studies at scheduled intervals.
Due to the large number of potential risk factors being tested in this study, there is a possibility of
identifying a factor that is statistically significant purely by chance. The prognostic factors identified in
this study will require validation in a subsequent study.
5.2
PRIMARY OBJECTIVE
The primary objectives of this protocol are to establish the incidence of CKD, metabolic syndrome and
osteopenia at one year following transplant.
5.3
SAMPLE SIZE, ACCRUAL AND STUDY DURATION
The study sample size is driven by the number of potentially eligible patients and the ability to estimate
the incidence of CKD, metabolic syndrome, and osteopenia following HCT. The sample size has been
justified based on the width (sufficiently narrow) of a 95% confidence interval on the 1-year (or 2-year)
incidence of a given late effect (Table 5.6). The accrual goal is 340 patients in 3 years. This is based
upon estimates from potential PBMTC participating centers with enrollment of 113 patients per year.
We estimate that approximately 850 patients will be eligible for enrollment during this period of time.
The number of potentially eligible patients was estimated from letters of commitment from PBMTC
centers. With a goal accrual of 340 patients, only 40% patient participation will be required to accrue on
schedule. It is estimated that 50% of the 340 enrolled patients will either not survive or will be lost to
follow-up prior to the two year assessment, i.e., approximately 170 patients will be available at two
years post-HCT for the estimation of the proportion of patients with each late effect.
5.4
INTERIM ANALYSIS AND STOPPING GUIDELINES
This is a prospective observational cohort study. There is no planned study intervention. There are no
planned interim analyses or stopping rules.
5.5
VARIABLES OF INTEREST
The following patient, disease, and treatment related variables will be studied.
Primary variables
CKD, metabolic syndrome, and/or osteopenia at one-year following HCT: Present vs. Absent
Other variables of interest
Patient related variables





Age at start of HCT conditioning: continuous variable
Gender: male vs. female
Lansky Play Performance Score/Karnofsky Performance Score: 90%- 100% vs. < 90%
History of smoking cigarettes in the past year: Yes vs. no
History of any of the following prior to or at the start of the HCT conditioning regimen:
 Congestive heart failure (EF <50%): Yes vs. no
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







Coronary artery disease without prior myocardial infarction: Yes vs. no
Hypertension: Yes vs. no
Stroke/cerebrovascular accident: Yes vs. no
Diabetes mellitus: Yes vs. no
Renal failure requiring dialysis: Yes vs. no
Acute or chronic kidney disease requiring medical treatment: Yes vs. no
Dyslipidemia: Yes vs. no
Osteoporosis: Yes vs. no
Disease and pre-HCT treatment related variables








Primary disease: ALL vs. AML/MDS vs. other
Disease status and number of complete remission at start of HCT conditioning: CR1 vs. > CR1
Cranial radiation prior to start of HCT conditioning regimen: yes vs. no
Chest radiation prior to the start of HCT conditioning regimen: yes vs. no
Total cumulative anthracycline chemotherapy: continuous variable
Bone mineral density: Z-score greater than 0 vs less than 0 to -1 vs less than -1
Fat mass: percentile as a continuous variable
Lean body mass (grams): continuous variable
Transplant and Post-Transplant variables















5.6
Conditioning regimen used including: TBI vs. no TBI
Donor type: related vs. unrelated
Degree of HLA matching: 8/8 vs. 7/8 for BM or PBSC, <= 4/6 vs. > 4/6 for UCB
Grade 2-4 acute GVHD: yes vs. no
Total number of days of corticosteroid therapy: continuous variable
Acute kidney injury or chronic kidney disease prior to day 100 and/or 1-year : yes vs. no
Hypertension treated with medication prior to day 100 andbetween day 100 and 1-year: yes vs.
no
Dyslipidemia prior to day 100 and/or 1-year : yes vs. no
Adiposity prior to day 100 and/or 1-year : yes vs. no
Stroke/seizure prior to day 100 and/or 1-year : yes vs. no
Diabetes/hyperglycemia requiring use of insulin or oral hypoglycemic medication prior to day
100 and/or 1-year : yes vs. no
Chronic GVHD: yes vs. no
Protein biomarker elafin in the urine: continuous variable (prior to the start of conditioning, day
30 +/- 7 days, day 100 +/- 21 days, day 180 +/- 21 days, one year +/- 45 days, and two years +/60 days)
Levels of fasting TG, LDL, HDL, insulin, and glucose greater than 95% percentile according to
Appendix C (baseline, day 100, 1 year, and 2 years)
Vitamin D deficiency: yes vs. no
ANALYSIS OF PRIMARY ENDPOINT
The primary aims of this protocol are to establish the incidence of CKD, metabolic syndrome and
osteopenia at 1-year and 2-years following transplant. The cumulative incidence curve of each late
effect will be presented, treating death and relapse/progression as a competing risks; patients for whom
the given late effect is not observed will be censored on the date of last contact. Late effects will be
descriptively summarized at 1-year and 2-years following transplant. The table below demonstrates
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that the width of a 95% confidence interval (CI) on the proportion of patients who have a particular late
effect (at either 1-year or 2-years), is sufficiently narrow. The sample size of 170 is based on the
estimate of 50% of enrolled patients being alive and available for analysis at two years following HCT.
Table 5.6. Width of 95% confidence interval on the incidence of a late effect
Confidence
Level
0.950
0.950
0.950
0.950
0.950
5.7
Sample Size
(N)
170
170
170
170
170
Actual Width of
CI
0.096
0.113
0.125
0.135
0.143
Proportion with
Late Effect
0.100
0.150
0.200
0.250
0.300
Lower Limit of
CI
0.059
0.100
0.143
0.187
0.232
Upper Limit of
CI
0.155
0.213
0.268
0.322
0.375
ANALYSIS OF SECONDARY ENDPOINTS
1. Univariate tests of association will be performed, separately for the 1-year and the 2-year post-HCT
endpoints, to identify potential risk factors for CKD, metabolic syndrome, and osteopenia. For
binary risk factors (see section 5.5), Fisher’s Exact test will be used. For continuous risk factors ,
a Wilcoxon rank-sum test will be used. Factors found statistically significantly prognostic will be
carried forward into multivariate analyses. To identify the factor or combination of factors
prognostic of the occurrence of a given late effect (CKD, metabolic syndrome, and osteopenia) at a
given time point (either 1-year or 2-years post HCT), we will use a logistic regression model. A
survival analysis approach was considered, but ultimately deemed not appropriate for this aim, due
to the lack of continuous monitoring over time for the occurrence of CKD, metabolic syndrome, and
osteopenia.
Conservatively assuming 140 patients with known data at 2-years, this sample size will be
sufficient to detect a difference of 17% in a two-sided Fisher’s exact test (5% versus 22%) if the
subgroups are of equal size (n=70 each) with at least 80% power and alpha=.05. However, if the
groups are of very unequal size (n=20 versus n=120), there will be more than 80% power to detect
a 31% difference (5% versus 36%), with alpha=.05. As a rule of thumb, the logistic regression
model will have sufficient power to identify one statistically significant risk factor for every 10
patients who report a given late effect; therefore, if there are 100 patients with known data for all
risk factors, we anticipate being able to identify 2-3 statistically significant risk factors in the
multivariable model.
2. Potential associations of systemic hypertension (presence/absence) with proteinuria, AKI, and
CKD, at day 100 and 1-year following HCT, will be tested using a Fisher’s Exact test.
3. The comparison of the GFR based on cystatin C and creatinine based estimating equations to
nuclear medicine GFR and/or 24-hour creatinine clearance will be performed as follows: eGFR will
be calculated using the cystatin C and creatinine based equations. For each equation, the resulting
eGFR will be compared to the GFR measured by nuclear medicine or 24-hour creatinine clearance
using a paired t-test. Linear regression modeling will be used to evaluate the relationship between
the estimated GFR and measured GFR, and the R2 will be calculated. Scatterplots will be
generated of eGFR versus GFR.
4. A generalized estimating equations (GEE) approach will be used to test for an association of elafin
levels over time with the presence/absence of CKD. In addition, the elafin level at each time point
will be tested for an association with the presence/absence of CKD using a Wilcoxon rank-sum test.
Elafin levels will also be descriptively presented using box and whisker plots at each time point.
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5. Descriptive statistics will be used to report levels of fasting TG, LDL, HDL, insulin, and glucose. At
each time point for each factor, the mean, standard deviation, minimum, and maximum will be
reported.
6. Change in body composition including BMD, fat mass, and lean body mass will be analyzed by
describing the distribution of the Z-scores at each time point and by conducting a paired analysis for
change.
7. Descriptive statistics will be used to report levels of 25-OH vitamin D, PTH, calcium, osteocalcin,
bone specific alkaline phosphatase, and urine N-telopeptide at the measured time points. Levels
will also be graphically presented using box and whisker plots at each time point.
8. Descriptive statistics will be used to report the cumulative incidence of each of the following:
hypertension, AKI, dyslipidemia, osteoporosis, albuminuria, proteinuria, obesity, adiposity, and
vitamin D deficiency.
9. Plasma samples will be banked in the repository, and a database will be developed. For each
specimen, data will be stored for the CRID number, date obtained, type of specimen, quantity, data
about consent for use of the specimen, and other items as needed. This specimen data will be able
to be linked to the clinical annotation data, for use in future investigation of HCT-associated late
effects.
5.8
ANALYSIS OF TERTIARY ENDPOINTS
Descriptive statistics will be used to report values for BMD (Z-score), BMI, and GFR. At each time point
for each factor, the mean, standard deviation, minimum, and maximum will be reported.
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Appendix A: Normal Blood Pressure in Children
Blood Pressure Tables for Children and Adolescents from the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, http://www.nhlbi.nih.gov/guidelines/hypertension/child_tbl.htm
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Appendix B: BMI Growth Charts
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Appendix C: Triglyceride and cholesterol levels based on age, race, and sex 83
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Appendix D: Waist Circumference 84
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Appendix E: Body Fat Percentiles 76
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