A Pilot Study Investigating the Effect of Supplementation with Milk Thistle on Hepatic Toxicity in Children Undergoing Treatment for Acute Lymphoblastic Leukemia - PowerPoint PPT Presentation

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A Pilot Study Investigating the Effect of Supplementation with Milk Thistle on Hepatic Toxicity in Children Undergoing Treatment for Acute Lymphoblastic Leukemia

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Preliminary Findings: Dietary Folate and Methotrexate (MTX) toxicity in children with acute lymphoblastic leukemia (ALL) Author: Elena Ladas Last modified by: – PowerPoint PPT presentation

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Title: A Pilot Study Investigating the Effect of Supplementation with Milk Thistle on Hepatic Toxicity in Children Undergoing Treatment for Acute Lymphoblastic Leukemia


1
A Pilot Study Investigating the Effect
of Supplementation with Milk Thistle on Hepatic
Toxicity in Children Undergoing Treatment for
Acute Lymphoblastic Leukemia
  • Elena J. Ladas, MS, RD, Bin Cheung, PhD, Susan
    Rheingold, MD and Kara Kelly, MD
  • Division of Pediatric Oncology, Columbia
    University
  • New York, NY

2
Background
  • Chemotherapy associated toxicity is the primary
    reason for dose reductions or withdrawal of the
    recommended therapy during the maintenance phase
    of therapy for children with ALL
  • Hepatic toxicity has been reported as a major
    reason for cumulative drug reductions
  • 66 of children with ALL encounter hepatic
    toxicity during the maintenance phase of therapy.
    (J Clin Oncol 1997 15(4)1560-1566)
  • Pediatric ALL patients with a cumulative
    withdrawal of MTX or 6-MP of greater than 10 of
    the maintenance therapy period had an increased
    risk of bone marrow relapse (MTXp0.009,
    6-MPplt0.00001) (Pediatric Hematology Oncology.
    8(4) 301-312. 1991)

3
Background
  • Surveys have found that the incidence of the use
    of complementary and alternative medicine (CAM)
    among children with cancer ranges between 10 to
    85
  • Milk thistle is the most commonly used self
    prescribed hepatoprotectant by children with ALL.
  • Milk Thistle, Silybum marianum, is an herbal
    plant that is widely used in Europe for the
    treatment of liver, biliary disorders, and for
    protection from hepatotoxins.

4
Milk Thistle Chemistry
Silymarin or Silymarin Group
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Dose and Form of Milk Thistle (Silybum marianum)
  • Dose 5.1mg/kg/day
  • Siliphos (Donated by Thorne, Inc.)
  • 80 mg capsules
  • Standardized to the silibinin content
    phosphatidycholine-bound

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Pre-clinical Investigations
  • Primary Objectives
  • Conduct in vitro experimentations to observe the
    effect of silibinin on growth of leukemia cells
  • Investigate the combination of silibinin and
    vincristine and l-asparaginase on the growth of
    leukemia cells

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Conclusions
  • When used at relevant or supraphysiological
    concentrations, silibinin causes no negative
    interactions with vincristine or L-asparaginase
    on CCRF-CEM T-cell ALL cells
  • At the higher concentration, silibinin is
    additive or synergistic with vincristine. This
    potentially beneficial interaction is not
    observed with L-asparaginase

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Pilot Clinical Study
  • Primary Objective
  • To determine the effect of milk thistle
    (Siliphos) in children with ALL with
    hepatoxicity (AST, ALT, TB) related to
    maintenance phase of therapy.

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Upon consent, Patient Randomized
  Day 0 of
Maintenance Day 0 of Maintenance - Begin
Siliphos for 28 days - Begin placebo for 28
days - Blood Collection (LFTS) - Blood
Collection (LFTs)

 
Day 28 of Maintenance Day 28 of
Maintenance - Discontinue Siliphos for 28 days
- Discontinue placebo for 28 days - Blood
Collection (LFTs) - Blood Collection (LFTs)
Day 56 of Maintenance Day 56 of
Maintenance - Blood Collection (LFTs) -
Blood Collection (LFTs)
 
   
14
Eligibility
  • Subjects between the age of 1 and 21 undergoing
    treatment for ALL and were in the maintenance
    phase of therapy
  • Subjects with grade 2 or higher hepatic toxicity
    (NCI Common Toxicity Criteria (Ver 2.0) on any
    one of three values
  • Exclusion Criteria
  • Patients with extrahepatic biliary obstruction,
    GI obstruction, malabsorption syndromes, or
    severe hepatic/kidney failure.

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Monitoring of Adverse Events
  • Subjects were contacted by phone or during a
    scheduled visit each week during the first 28-day
    intervention and administered brief survey
  • The medical records were reviewed weekly for
    reports of toxicity during the supplementation
    period

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Purity and Stability Testing
  • Purity
  • Siliphos and placebo were shipped with a COA
  • Purity and quality assurance studies were
    performed, with regard to heavy metals,
    bacterial and fungal counts, pesticide residues,
    potential contamination with prescription
    pharmaceuticals
  • Analysis of each batch of milk thistle was also
    analyzed to confirm dosage of capsules
  • Stability
  • Quantify Siliphos for content of silibinin
    isomers, silybin A and B, and monitor stability
    of its composition at the initiation and at the
    end of the study.

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Demographic Data
Characteristics Milk Thistle (N24) Placebo (N26)
Mean age, years Median Range 8.7 5.1 7.5 1.4-18.9 7.0 3..2 6.2 2.5-14.3
Gender Male Female 14 10 15 11
Race Caucasian Black, Not Hispanic Hispanic Other 15 1 5 2 19 0 4 3
Risk Group Standard Risk High Risk 15 9 17 9
No significant differences in age, gender,
protocol, or race were observed.

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No significant differences in the incidence of
toxicity
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Siliphos significantly reduced liver function
tests
P lt 0.05


AST
ALT
20
Patients treated with Siliphos had a greater
reduction in total bilirubin
p lt 0.0069
P lt 0.0069
21
Conclusions
  • We found that supplementation Siliphos was
    associated with a significant reduction in AST.
  • We observed a trend in the reduction of ALT.
  • Subjects in the Siliphos group had a larger
    reduction in serum total bilirubin during the
    28-day supplementation period.

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Next Steps
  • A larger, randomized, double-blind, controlled
    clinical trial in children undergoing treatment
    for ALL through COG
  • Conduct short term in vitro cell culture of human
    ALL xenografts to assure that anticipated plasma
    levels of silibinin do not adversely stimulate
    proliferation of cells in a culture setting most
    representative of human disease
  • Conduct in vivo xenograft studies of ALL
    xenografts in the NOD/SCID obese/diabetic mouse
    model to investigate if silymarin attenuates
    hepatotoxicity induced by chemotherapeutic drugs
    does not accelerate the growth of pediatric ALL
    in immune-deficient mice, and does not decrease
    the efficacy of chemotherapeutic drugs in
    xenograft models of pediatric ALL

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Acknowledgements
  • Kara Kelly, MD
  • Principal Investigator, Columbia University
  • Robert McArthur
  • PharmD
  • Columbia University
  • Deborah Hughes,
  • Research Assistant, Integrative Therapies
    Program for Children with Cancer
  • Columbia University
  • Susan Rheingold, MD,
  • Co-Investigator
  • Childrens Hospital of Philadelphia
  • David Kroll, PhD,
  • Co-Investigator
  • Research Institute Triangle
  • North Carolina
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