Kevin C. Oeffinger, MD

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Cardiovascular Riskand Metabolic Syndromein
Young Adult Survivorsof Childhood ALLProject
ALLIFE

• Kevin C. Oeffinger, MD
• R01 CA 100474
• and the Adleta Foundation

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Premature CVD and Childhood ALL Potential
Mechanisms
CVD
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Project ALLIFE Acute Leukemia Lifestyle
Intervention For Everyday
Young adult survivors of childhood acute
lymphoblastic leukemia
Phase One Determine prevalence of CVD risk
factors and metabolic syndrome
Phase Two Test the effectiveness of a Lifestyle
intervention intended to increase the level of
physical activity and improve cardiorespiratory
fitness
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Project ALLIFE Phase One

• Cross-sectional design
• Inclusion criteria
• ALL diagnosed age 0-20 yrs
• gt 2 yrs off therapy
• Diagnosed, treated, or followed at Childrens
  Medical Center, Dallas between 1970-2000
• Cook Childrens Medical Center of Ft. Worth -
  participants on a shared DFW-1 protocol
• Population-based comparison group
• Age-, gender-, race-matched controls
• Dallas Heart Disease Prevention Project

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Cardiovascular Risk Factors

• Insulin resistance
• Fasting glucose and insulin
• Homeostatic model assessment (HOMA_IR)
• Defined insulin resistance as HOMA_IR gt 2.86
• Dyslipidemia
• LDL, HDL, triglyceride
• LDL pattern, HDL and LDL subspecies
• Lp(a)
• Elevated blood pressure
• Cardiac inflammatory markers
• high sensitivity C-reactive protein (hs-CRP)
• IL-1B, IL-6, IL-10, TNF-a
• Obesity
• Physical inactivity

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Metabolic Syndrome

• Clustering of obesity, insulin resistance,
  dyslipidemia, and elevated blood pressure
• Modified ATP III Criteria for metabolic syndrome
  - 3/5 criteria
• Abdominal obesity waist circumference
• Triglycerides gt 150 mg/dL
• HDL lt 50 mg/dL (females) lt 40 mg/dL (males)
• Blood pressure gt 130/85
• Fasting glucose gt 100 mg/dL

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Participants and Non-participants

• ALLIFE Non-P P
• Gender, females 55 39 0.003
• Current age, yrs 23.8 24.8 0.4
• Age at ALL dx, yrs 6.3 4.3 0.01

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Demographics for ALLIFE (N118)
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Percent with selected CVD risk factors
Dyslipidemia (LDL, TG, HDL) Dyslipidemia
plus HDL2, LDL pattern B Insulin
resistance (HOMA_IR gt 2.86) Elevated BP (gt
130/85) Elevated hs-CRP (gt 3.0 mg/dl)
Percent
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Obesity Measures

• Body mass index (BMI)
• Waist circumference
• DXA for total body fat
• Leptin level, leptin kg/fat mass
• CT for abdominal/visceral fat distribution

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Computed Tomography (CT)

• Abdomen
• Volumes of visceral ( VAT) and subcutaneous (SAT)
  fat
• L3-L4 to L4-L5 to calculate total volume of each
  compartment
• VAT associated with IR

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Prevalence of Obesity in Participants by Body
Mass Index
Percent
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Waist Circumference
DXA Body Fat
Adj R2 0.64
Adj R2 0.86
Visceral Adipose Tissue
Subcutaneous Adipose Tissue
Adj R2 0.61
Adj R2 0.82
Females - Body Mass Index
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Waist Circumference
DXA Body Fat
Adj R2 0.55
Adj R2 0.84
Visceral Adipose Tissue
Subcutaneous Adipose Tissue
Adj R2 0.35
Adj R2 0.78
Males - Body Mass Index
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Physical Activity Measures

• VO2 submaximal and maximal testing
• 7-day Physical Activity Recall (PAR)
• SensorWear x 8 days
• Accelerometer with heat sensor
• Steps
• Minutes in mild, moderate, vigorous activity
• Total energy expenditure

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VO2 Maximum Testing

• AHA Fitness Classification Females
  Males
• (ml/kg/min)
• Low lt 23.5, lt 24.5 51 12
• Fair lt 30.4, lt 33.4 27 29
• Avg lt 37.4, lt 42.4 17 39
• Good lt 48.4, lt 52.4 5 20
• High gt 48.4, gt 52.4 0 0
• Age and gender-specific norms for VO2 max values.

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VO2 Maximum Testing

• AHA Fitness Classification Females
  Males
• (ml/kg/min)
• Low lt 23.5, lt 24.5 51 12
• Fair lt 30.4, lt 33.4 27 29
• Avg lt 37.4, lt 42.4 17 39
• Good lt 48.4, lt 52.4 5 20
• High gt 48.4, gt 52.4 0 0
• Age and gender-specific norms for VO2 max values.

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Percent with Criteria for Metabolic
Syndrome Criteria Waist Circ, Glucose, TG, HDL,
BP
Percent
0 1 2
gt 3
Criteria for Metabolic Syndrome
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Percent with Criteria for Metabolic
Syndrome Criteria Waist Circ, Glucose, TG, HDL,
BP
Females 42 Males 29
Percent
0 1 2
gt 3
Criteria for Metabolic Syndrome
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Percent with a CVD Risk Factor (IR, Lipid, BP,
BMI gt 25, PA lt 150 min/week, hs-CRP gt 3.0)
Percent
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CVD Risk Factors
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Treatment-Related Factors

• Outcome gt 3 (of 6) CVD risk factors (vs 0-2)
• Predictor variables considered
• Age at study
• Age at cancer diagnosis
• Interval from cancer diagnosis to study
• Cumulative anthracycline dose
• Cumulative IT MTX dose
• Dexamethasone, yes/no
• Cranial radiotherapy by total dose
• Race and ethnicity
• Stratified by gender
• Bivariate followed by logistic regression analysis

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Treatment-Related Factors

• Females
• gt 20 Gy CRT vs 0-19 Gy CRT
• OR 13.3 95 CI, 1.6-108.2 p0.015

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Treatment-Related Factors

• Females
• gt 20 Gy CRT vs 0-19 Gy CRT
• OR 13.3 95 CI, 1.6-108.2 p0.015
• Males
• No treatment-related factors associated with
  outcome

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CVD Risk Factors by Cranial Radiotherapy

• Females
• 0-19 Gy gt 20 Gy
• N47 N19
• LDL 99.7 118.2
• HDL 51.8 48.3
• TG 92.9 148.1
• HOMA 3.6 6.4
• hs-CRP 3.0 6.8

Males 0-19 Gy gt 20 Gy N42
N10 111.4 128.0 44.1 46.6 140.2 147.7
3.8 5.0 2.6 4.3
p lt 0.05 p lt 0.01 p lt 0.001
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Obesity Measures by Cranial Radiotherapy

• Females
• 0-19 Gy gt 20 Gy
• N47 N19
• BMI 27.3 33.8
• Waist, cm 89.4 100.0
• Fat 35.7 43.4
• VAT 0.18 0.42
• SAT 0.99 1.36
• Leptin 20.2 29.3
• Leptin/kg 0.73 0.81

Males 0-19 Gy gt 20 Gy N42
N10 26.2 28.7 89.1 97.9 22.4 28.9
0.28 0.44 0.83 1.15 6.6
14.6 0.31 0.48
p lt 0.05 p lt 0.01 p lt 0.001
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Females
Females
Adj R2 0.003
Adj R2 0.15
VO2 Max (ml/kg/min)
VO2 Max (ml/kg/min)
Males
Males
Adj R2 0.15
Adj R2 0.17
VO2 Max (ml/kg/min)
VO2 Max (ml/kg/min)
Anthracycline (mg/m2) Cranial Radiotherapy (Gy)
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Summary

• CVD risk factors were common in this population
  of ALL survivors
• CRT, especially in females, was associated with
  an increase in prevalence of CVD risk factors
• In ALL survivors treated without CRT, CVD risk
  factors were common

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Summary (2)

• Visceral adipose tissue, especially in females,
  was associated with insulin resistance and
  elevated hs-CRP levels
• For perspective, this cohort will be compared
  with a population-based cohort (DHD study)
• Interventions targeted at decreasing (or
  preventing) obesity and visceral adipose tissue
  may lower risk for premature CVD

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Project ALLIFE - Acute Leukemia Lifestyle
Intervention For Everyday

• UT Southwestern
• Co-Investigators
• Ronald Victor, MD
• Peter Snell, PhD
• Ross Querry, PhD
• Angela Shoup, PhD
• Research Staff
• Sandy Brooks, LD
• Alicia Turoff, MPH
• Jessica Scarf
• Janice Rookstool
• GCRC
• Carol Parcel, RN
• Beverley Huet, MS
• Sharon Haynes, RN
• Robert Butsch
• Ancillary MRI study
• Sharon Reimold, MD
• Jennifer Wright, MD

• CMC, Dallas
• Debra Eshelman, CPNP
• Judy Watkins
• Cook CMC, Ft. Worth
• Jeffrey Murray, MD
• Lisa Bashore, CPNP
• Cooper Research Institute
• Timothy Church, MD
• Radim Jurca, PhD
• Alex Jordan, MS
• Erin Sinclair
• Klein Buendel
• Andrea Dunn, PhD
• Queens University
• Robert Ross, PhD
• Peter Janiszewski

• Advisory Committee
• Anna Meadows, MD
• Leslie Robison, PhD
• Marilyn Wright, MEd
• Naomi Winick, MD
• George Buchanan, MD
• David Buller, PhD
• Khashayar Sakhaee, MD

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Females
Males
Adj R2 0.34
Adj R2 0.32
HOMA_IR
HOMA_IR
Adj R2 0.03
Adj R2 0.40
hs-CRP
hs-CRP
Visceral Adipose Tissue Volume