CNS-Directed Therapy for Childhood Leukemia

Neurodevelopmental Consequences of Neurologic Injury

BRAIN Initiative

1. The Brain in Actiona. dynamic picture of the functioning brainb. molecular genetics

2. Advancing Human Neurosciencea. maximize collection of human samples

for research on mechanisms of human brain disorders

3. Human Neural Technology b. technology to restore lost function

Acute Lymphoblastic Leukemia

1. One in 330 children is diagnosed with cancer by age 20

2. One in 530 young adults 20 to 39 years of age is a childhood cancer survivor

3. Most prevalent cancer among children &

adolescents is ALLa. once fatalb. 5 year survival approaches 90%

Improved Survival from ALL

1. Use of multi-agent therapy

2. Know risk factors for recurrencea. minimal residual diseaseb. treatment intensity matched to

recurrence risk

3. Aggressive CNS-directed treatment for subclinical disease in the braina. primary site of initial disease relapse

What are the Consequences of CNS-Directed Therapy?

1. Neurodevelopmental and academic problems

2. Experienced by up to 60% of ALL survivorsa. Memoryb. Visual spatial abilitiesc. fine motor speedd. attentione. processing speedf. academic achievement

3. Associated with secondary effects on g. psychological well being (anxiety, depression)h. social & adaptive skillsi. vocational success

Cognitive Measure

Post-Induction

Mean SD

Continuation

Mean SD

End of Therapy

Mean SDVisual SpatialSkills 97.07 13.95 94.14 16.83 89.6 8.10

Fine Motor Speed*

-1.19 1.28 -0.42 1.02 -0.39 1.23

Visual Working Memory* -0.17 1.39 -0.08 0.99 -0.34 0.95

Verbal Working Memory* -0.35 0.96 -0.25 0.83 -0.39 0.75

Processing Speed* -0.80 1.68 -0.68 1.27 -0.67 0.98

Cognitive Abilities Over Time

* reported as Z scores with mean of 0 and SD of 1

Cognitive Abilities can Impact Academic Outcomes

Visual Motor

Integration

Visual Memory

Verbal Memory

Fine Motor Abilities

Letter/Word Identification

r = 0.748p < 0.001

r = 0.624 p < 0.001

r = 0.534 p < 0.001

r = 0.465 p < 0.001

Calculationr = 0.536p < 0.001

r = 0.340p = 0.015

r = 0.321p = 0.020

r = 0.290p = 0.040

Why do children with ALL have long-term neurodevelopmental & academic problems?

CNS Directed Chemotherapy Model of Neurologic Injury : Oxidative Stress & Apoptosis

Oxidative Stress & Apoptosis Biomarkers

1. Oxidized phospholipids by HPLC with diode array detection

a. 206 detects unoxidized phospholipidsb. 234 detects oxidized phospholipids

2. Caspase enyzme activity by Promega Glo™ assays

a. capase 8 & 9 initiate apoptosisb. caspase 3/7 execute apoptosis

CSF Phospholipid Composition in Children

Series10

10

20

30

40

50

60

70

PI (2.7%)

PE (3.6%)

PA (1.5%)

PC (61.4%)

SM (24%)

LPC (6.7%)

Minutes

0 5 10 15 20 25 30 35 40 45 50 55 60

mA

U

-250

-200

-150

-100

-50

0

50

100

150

200

mA

U

-250

-200

-150

-100

-50

0

50

100

150

200

Minutes

0 5 10 15 20 25 30 35 40 45 50 55 60

mA

U

-40

-30

-20

-10

0

10

20

30

40

50

60

mA

U

-40

-30

-20

-10

0

10

20

30

40

50

60

Unoxidized Phospholipids 206nmPI

PI

PC

PC

Oxidized Phospholipids 234nm

Oxidized PC by Treatment Phase

0

5

10

15

20

25

Peak

are

a c

ount

x 1

00

0

F = 22.135; df = 4; p < 0.001

Oxidized PI by Treatment Phase

Diagnosis Day 8 Induction Post-induction Continuation0

200

400

600

800

1000

1200

1400

1600

1800

2000

Peak

are

a c

ount

x 1

00

0

F = 16.747; df = 4; p < 0.001

Diagnosis Induction Post-Induction Continuation0

20

40

60

80

100

120

Caspase Activity by Treatment Phase

Caspase 8(Units/L)

Caspase 9(Units/mL)

Caspase 3/7(Units/L)

Oxidative Stress Biomarkers of Neurologic Injury

Oxidized PIVisual Spatial/Fine Motor

Abilities

Induction r = - 0.24; p < 0.05

Post Induction r = - 0.29; p < 0.05

Continuation r = - 0.32; p < 0.05

Oxidized PCTreatment-related

SymptomsPost-Induction r = 0.33; p < 0.05

Continuation r = 0.52; p < 0.01

Human Neural Technology Development

Can we restore cognitive and academic abilities

in children with ALL?

Improving Academic Outcomes: Math Intervention

Determine if Math

Intervention prevents

declines in academic

math scores in children with

ALL

Nonverbal Working Memory: Changes over Time by Group

F [2, 29] = 5.53, p < =.009

Math Skills in Intervention Group: Changes Over Time

F [2, 29] = 12.47, p <0.001