Title: Cognitive Neurotoxicity in Children Treated for Acute Lymphoblastic Leukemia Using HighDose Methotre
1Cognitive Neurotoxicity in Children Treated for
Acute Lymphoblastic Leukemia Using High-Dose
Methotrexate
- Daniel Armstrong, Ph.D.
- Mailman Center for Child Development Department
of Pediatrics - University of Miami Miller School of Medicine
- And
- Holtz Childrens Hospital at the
- University of Miami/Jackson Medical Center
2Background
- Prior to 1986, CNS prophylaxis for ALL involved
CRT (18-24 Gy) with or without intrathecal
methotrexate - Cognitive neurotoxicity was common, with learning
difficulties in the areas of processing speed,
visual-motor integration, attention and
concentration, and memory. Math abilities most
affected
3Background
- Most of the research on cognitive neurotoxicity
associated with MTX has been involved the
POG-CCG-COG approach to ALL treatment - There are few data on cognitive neurotoxicity
looking at other approaches (e.g., Capizzi BFM
with 5g/m2 X 4) to ALL treatment
4Background
- POG 8602 eliminated CRT and used triple
intrathecal chemotherapy (TIT) for CNS
prophylaxis (methotrexate, hydrocortisone, ARA-C) - Transient white matter changes noted early on MR,
but these resolved (Nitschke et al, 1990). - No cognitive changes noted at 1-year follow-up
after diagnosis, but difficulties in delayed
recall, general non-verbal abilities, attention,
motor speed, and visual motor integration found
at completion of treatment (Brown et al, 1992) - Females at more likely to have cognitive deficits
5Background
- POG 9005 compared intermediate dose IV-MTX
(1g/m2) with oral MTX in different combinations
with mercaptopurine (oral vs. IV). - The original study involved comparison of TIT vs
MTX only for CNS prophylaxis, but all shifted to
TIT after higher than anticipated CNS relapse
with MTX only - Acute neurotoxicity (seizures, imaging
abnormalities) found for 7.8 of 1304 patients
(Mahoney et al., 1998).
6Background
- Limited institution study involving 54 children
treated on POG 9005 - No acute neurotoxicity
- All received non-contrast CT, Neuropsychological
Evaluation
7Background
- 40 had CT abnormalities
- Calcifications 50
- 76 at the Gray-White Junction
- 8 at lateral ventricles
- 6 frontal
- 4 basal ganglia, parietal, or temporal
- White Matter Changes 30
- 55 peri-ventricular
- 30 at lateral ventricles
- 7 frontal
- 7 posterior white matter
- Both Calcifications and WMC 20
8POG 9005 Outcomes
9POG 9005 Percent Classifications of Verbal IQ,
Performance (non-verbal) IQ, Reading, Math,
Visual-Motor Integration, and Processing Speed
10POG 9005 Percent of Classifications Based on
Memory Scores (WRAML)
11POG 9005 Percent Classification by Conners
Continuous Performance Scores (CPT-Attention)
12Background
- POG 9605 expanded on 9005, with HD-MTX and TIT
- Single institution study (Montour-Proulz et al.,
2005) with 24 children found - Mean VIQ87, PIQ84, Verbal Memory83, Visual
Memory88. - 78 had MR abnormalities at some point in study
- COG (ALTE0131) late effects study involving
MR-FLAIR and Neuropsychological function now
underway
13Questions
- Mechanism
- Vascular leading to calcification
- Anti-folate effects of MTX
- Disruptions in the folate/adenosine pathways
- Elevated homocysteine (Kishi et al., 2003 Quinn
et al., 2004 - White matter changes/demyelination
- Pharmacogenetic risk
- Why only 40 affected?
14The Neurodevelopmental ModelTreatment-Academic
Linkages
Interrupted Myelination
Processing Speed
Cranial Radiation
Failure of Connecting Structure Development
Reading (Comprehension)
Attention Concentration
Chemotherapy (MTX, Steroids)
Visual-Motor Integration
Math (Calculations)
Calcification
Surgery
Visual Memory
Handwriting
Structural Damage
Organization Planning
Shunt Seizure Genetics
Sensory Impairment
Other Impairment
15Questions
- Can outcomes be predicted using an interactive
model of defined risk (genetic, pharmacologic,
structural, and acute events) and
neurodevelopmental trajectory?
16Emerging Cognitive Deficits Developmental
Patterns
Gross Motor Skills
Language Skills
Attention
Fine Motor Skills
Visual-Spatial Motor Skills
1
2
3
4
5
6
7
8
9
17Emerging Cognitive Deficits Developmental
Patterns
Gross Motor Skills
Language Skills
Attention
Fine Motor Skills
Visual-Spatial Motor Skills
1
2
3
4
5
6
7
8
9
18Methotrexate NeurotoxicityProjects
- Overall Project Goals
- Determine the incidence and severity of MTX
neurotoxicity associated with Capizzi and HD-MTX
treatment - Identify risk factors and possible mechanisms for
neurotoxicity associated with MTX that lead to
cognitive impairment
19Methotrexate NeurotoxicityProject Purposes
- Project 1 Describe neurocognitive development in
children with ALL at 3 time points - Project 2 Identify host polymorphisms that may
predict who, among the treated population, are at
increased risk for neurocognitive toxicity. - Project 3 Determine whether acute, transient
episodes of neurologic toxicity reflect similar
biochemical vulnerability and predict
neurocognitive loss. - Project 4 Study the pathophysiology of
neurologic dysfunction though an assessment of
the impact of MTX on folate dependant biochemical
pathways. - Project 5 Identify areas of selective
vulnerability within the CNS that may predict
and/or correlate with neurocognitive outcome
using diffusion tensor imaging.
20Methotrexate NeurotoxicityCOG AALL0232 AALL0434
- Enroll 432 children with high risk ALL treated on
AALL0232 or AALL0434, 72 sibling controls - Both Studies involve comparison of HD-MTX with
Capizzi Methotrexate for Consolidation - AALL0232 also compares dexamethasone with
prednisone during induction - AALL0434 adds Nelarabine
21Neurocognitive Outcomes Project
- Design
- Prospective, repeated measures design with
neurocognitive function as the primary outcome
variable (T1 end of induction, T2 12 months
after remission T3 12 months off-treatment) - Neurocognitive Outcomes
- SNP modeling
- Folate dependent biochemical pathways
- Diffusion Tensor imaging
- Acute neurotoxic events
22Neurocognitive Outcomes Project
- 2 age cohorts
- Younger (12.0 months-155.9 months at diagnosis)
- Older (156 months-216 months at diagnosis)
- Each age cohort sub-grouped by age at diagnosis,
with random distribution between Capizzi and
HD-MTX arms
23Methotrexate Neurotoxicity Study
- Areas of function assessed
- Global Intellectual function (IQ)
- Memory
- Attention
- Language (fluency, vocabulary)
- Planning and Organization
- Achievement (math and reading)
- Adaptive Behavior and Adjustment
24Methotrexate Neurotoxicity Study
- All children in the Younger Cohort will be
evaluated with the same primary test (WISC-IV) at
T3 the same applies to the Older Cohort
(WAIS-III at T3) - The evaluation strategy for primary outcome is
also applied to areas of specific function, so
that cross age samples can be compared at the
same time point using the same tests
25Methotrexate Neurotoxicity StudyNeurocognitive
Outcomes Hypotheses
- Hypothesis 1 Neurocognitive function at T3 will
be significantly lower in children treated with
HD-MTX than in children treated with LD-MTX. - Hypothesis 2 Neurocognitive function at T3 will
be significantly lower in the Younger than Older
Cohort, with a significant interaction between
age at diagnosis and MTX exposure (HD vs. LD). - Hypothesis 3 Within the Younger Cohort (Age
Groups 1, 2, 3), younger age at diagnosis will
result in lower neurocognitive function at T3
within both HD and LD MTX arms. - Hypothesis 4 Children in the Younger Cohort
will have significantly lower scores on measures
of specific function (memory, attention,
language, processing speed, planning and
organization, and achievement) than those in the
Older Cohort. - Hypothesis 5 Age at diagnosis, MTX dose (HD vs
LD), and the slope of neurocognitive function
between T1 and T2, and neurocognitive function at
T2 will be predictive of neurocognitive function
at T3.
26Concluding Points
- Neurocognitive toxicity is no longer seen as a
rare event. It is now a significant late effect.
However, we dont know to what degree this
applies to treatment approaches outside that of
the POG model of the 1990s. The opportunity to
both prospectively model and compare different
MTX approaches is unprecedented. - We hope that this new study will enable us to
define the mechanisms of effect, leading to
modifications in treatment, development of
prevention strategies, or early identification
for preventive behavioral or educational
intervention