Title: A Pilot Study Investigating the Effect of Supplementation with Milk Thistle on Hepatic Toxicity in Children Undergoing Treatment for Acute Lymphoblastic Leukemia
1A 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
2Background
- 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)
3Background
- 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.
4Milk Thistle Chemistry
Silymarin or Silymarin Group
5Dose 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
6Pre-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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11Conclusions
- 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
12Pilot 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.
13 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)
14Eligibility
- 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.
15Monitoring 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
16Purity 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.
17Demographic 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.
18No significant differences in the incidence of
toxicity
19Siliphos significantly reduced liver function
tests
P lt 0.05
AST
ALT
20Patients treated with Siliphos had a greater
reduction in total bilirubin
p lt 0.0069
P lt 0.0069
21Conclusions
- 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.
22Next 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
23Acknowledgements
- 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