Cognitive Neurotoxicity in Children Treated for Acute Lymphoblastic Leukemia Using HighDose Methotre

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Cognitive 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

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Background

• 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

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Background

• 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

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Background

• 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

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Background

• 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).

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Background

• Limited institution study involving 54 children
  treated on POG 9005
• No acute neurotoxicity
• All received non-contrast CT, Neuropsychological
  Evaluation

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Background

• 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

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POG 9005 Outcomes

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POG 9005 Percent Classifications of Verbal IQ,
Performance (non-verbal) IQ, Reading, Math,
Visual-Motor Integration, and Processing Speed
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POG 9005 Percent of Classifications Based on
Memory Scores (WRAML)
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POG 9005 Percent Classification by Conners
Continuous Performance Scores (CPT-Attention)
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Background

• 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

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Questions

• 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?

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The 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
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Questions

• Can outcomes be predicted using an interactive
  model of defined risk (genetic, pharmacologic,
  structural, and acute events) and
  neurodevelopmental trajectory?

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Emerging Cognitive Deficits Developmental
Patterns
Gross Motor Skills
Language Skills
Attention
Fine Motor Skills
Visual-Spatial Motor Skills
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Emerging Cognitive Deficits Developmental
Patterns
Gross Motor Skills
Language Skills
Attention
Fine Motor Skills
Visual-Spatial Motor Skills
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Methotrexate 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

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Methotrexate 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.

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Methotrexate 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

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Neurocognitive 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

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Neurocognitive 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

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Methotrexate 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

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Methotrexate 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

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Methotrexate 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.

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Concluding 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