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Amie DavéNovember 16, 2007
Columbia College of Physicians and SurgeonsMorgan Stanley Children’s Hospital of New York- Presbyterian
New York University School of Medicine
Vincristine in Cancer Therapy Vinca-alkaloid derived from the periwinkle plantIntegral part of many pediatric protocols
ALL, Hodgkin’s disease, non-Hodgkins lymphoma, rhabdomyosarcoma, neuroblastoma, Ewing’s sarcoma, Wilms tumor
Mechanism of vincristine (VCR)Binds to tubulin disrupts microtubule function
mitotic arrest & cell deathInterfere with many biochemical processes: amino acid
uptake, inhibition of protein, DNA, & RNA synthesis, disrupts lipid & glucose metabolism
Vincristine-Induced NeuropathyNeurotoxicity is the dose-limiting toxicity of VCR therapyManifests as a sensory and/or motor neuropathyPresentation of neuropathy in children
Paresthesias, numbness, loss of proprioception, gait disturbances
More difficult to detect May be subtle
Believed to be related to cumulative dose in adults
Glutamine Neutral non-essential amino acid, frequent use as a
nutritional supplementGlutamine depletion over time in cancer patients May have a promising role in prophylaxis against VCR-
induced neuropathyProposed mechanisms of neuroprotectant effect
Related to circulating nerve growth factor (NGF) levels; glutamine’s ability to upregulate NGF mRNA
Glutamine enhances microtubule formation and/or stability
Low toxicity
Study Objectives Eligibility Criteria Evaluate effect of glutamine on
VCR-mediated antitumor efficacy in vitro
Describe the incidence of VCR-induced peripheral neuropathy in pediatric oncology patients
Investigate the efficacy of glutamine in ameliorating VCR-induced peripheral neuropathy
To investigate the effect of glutamine on serum nerve growth factor and glutamine levels
InclusionAges 5 to 21 yearsAbility to complete baseline
assessmentDiagnosis of leukemia or solid
tumors and expected to receive ≥ 15 mg/m2 of VCR over 30 weeks
Exclusion Primary CNS tumors or CNS
metastasesRecurrent disease Grade II, III or IV neurological
status by the NCI CTC 3.0 on clinical exam
Already received > 8mg/m2 of VCR during therapy at the time of consent
Study Instruments
Purdue Pegboard Test
Symbol Digits Test
Hand DynamometerGrip Strength
Study Design Double-blind, randomized, placebo-controlled trial
Baseline
Neurological Statusevaluated every 3 weeks
Meet criteria Randomization
Glutamine Placebo
Day 0
Day 42
Day 21
Day 0
Day 42
Day 21
Neurological Assessments• Clinical exam• Purdue Pegboard Test• Symbol Digits Test• Grip Strength Test
Blood Collection• Serum NGF• Serum glutamine • Baseline, Day 0, 21, & 42
Day 21 - discontinuesupplement
Randomization Criteria• Clinically progressive neurological findings
• Increase in one toxicity grade by the NCI CTC 3.0 on clinical exam
or• Clinically progressive neuropsychological findings
• ≥ 1/2 SD from patient’s own baseline score on any of the instruments that measure fine and gross motor function
Glutamine dose 6 g/m2 (max of 10 g/dose) BID
In vitro testingDavid J. Kroll, Ph.D. Senior Research PharmacologistResearch Triangle Park, NC
Physiologic levels of glutamine: 500 – 600 µMCCRF-CEM human T-cell leukemia cellsThe effects of 0.5, 2, 5, and 10 mM of glutamine on
cell cycle distributioncellular growth ratesensitivity to vincristine cytotoxicitysensitivity to L-asparaginase cytotoxicity
Results – In vitro testing Effect of glutamine culture conditions on growth of
CCRF-CEM human T-cell leukemia cells
Days
0 1 2 3 4 5
cel
l nu
mb
er/m
L X
10,
000
0
50
100
150
200
250
0.5 mM Gln2 mM Gln5 mM Gln10 mM Gln
Results – In vitro testing No effect of glutamine on cell cycle distribution
Sub G0 G0/G1 S G2/M
0.5 mM Gln 2.70 ± 0.85 46.06 ± 1.31 21.05 ± 0.45 30.13 ± 1.59
2 mM Gln 3.81 ± 0.70 46.55 ± 2.06 20.69 ± 0.40 28.81 ± 1.85
5 mM Gln 3.78 ± 1.76 47.01 ± 2.53 20.81 ± 0.28 28.17 ± 2.17
10 mM Gln 2.25 ± 0.19 45.45 ± 0.67 21.36 ± 0.16 30.90 ± 0.59
Results – In vitro testing No effect of glutamine on vincristine sensitivity in CCRF-CEM
cells
Vincristine IC50 (nM)
0.5 mM Gln 0.695
2 mM Gln 0.740
5 mM Gln 0.772
10 mM Gln 0.791
Results – In vitro testing Effect of glutamine on
CCRF-CEM response tovincristine
-10 -9 -8 -7 -60
25
50
75
1000.5 mM glutamine2 mM glutamine5 mM glutamine10 mM glutamine
log [vincristine] (M)
% c
ellu
lar
surv
ival
Clinical Trial Demographics 23 patients, 3 removed, 2 on observationAges 5 – 19 years
Mean 9.9, Median 8.510 males, 8 femalesDiagnosis
ALL – 16 Rhabdomyosarcoma – 2Ewings sarcoma – 2Wilms tumor – 2 Hodgkin’s Disease – 2
Results – RandomizationCriteria for randomization met in first 18 of 18 patientsCriteria met by
Clinical exam – 5 patientsNeuropsych. Testing – 6 patientsBoth – 7 patients
VCR-related neuropathy is prevalent in children with overt progression by clinical exam in 67% May be greater if in fact neuropsych. testing is picking up
signs at an earlier stage
Results – Neuropsych. TestingPotential practice effect with Symbol Digits test
Neuropsychologic Test Mean change in z-
score* Range
Purdue Pegboard - Dominant -0.1 -2.5 to 1.72Purdue Pegboard - Non-dominant -0.54 -2.68 to 1.83Purdue Pegboard - Both -0.7 -2.34 to 1.11
Hand Dynamometer - Right -0.02 -1.76 to 1.71Hand Dynamometer - Left -0.46 -2.38 to 0.77
Symbol Digits† 0.89 .-0.54 to 2.84*Negative score indicates decline (z-score at randomization minus baseline z-score) from baseline to randomization test
†Ten patients administers symbols digits test, no norms for patients age five
Results – Cumulative VCR Cumulative dose of approximately 6 mg/m2 required for
detection of signs by clinical exam or neuropsych. testing in all but one patient
No difference in number of days to randomization between patients with ALL compared to other diseases
It is the cumulative dose as opposed to dose-intensity (mg/m2/28-day interval) that determines randomizationAmong six patients that received 6 mg/m2 ± 0.5, dose
intensity varied from 2.5 to 5.8 mg/m2/28-day interval
Results – Serum glutamine levelsNo significant difference found between glutamine levels at baseline and
at time of randomization (Z=-0.31, p=0.76)Significant correlation between baseline and the change in glutamine
(rho=-0.531, p=0.034)
Results – Serum glutamine levelsNo significant differences between ALL and other
diseases
Results – Glutamine & time to randomization Significant difference in the number of days to
randomization between patients who had a decrease and increase in glutamine (Z= -2.119, p=0.034) Decrease – mean 80.9 days, SD=36.96 Increase – mean 49.0 days, SD= 19.71
Findings No current evidence to suggest any adverse effect of glutamine on CCRF-
CEM leukemia cell growth, cell cycle distribution, or sensitivity to vincristine even at 20 times normal circulating concentrations
First 18 of 18 patients met criteria for randomization 12 patients randomized due to progression of score on clinical exam
Cumulative dose of approximately 6 mg/m2 required for detection of signs by clinical exam or neuropsych. testing
No differences in in glutamine levels between baseline and randomization No difference between patients with ALL and other diseases
Trends in glutamine levels may help predict who develops neuropathy
AcknowledgmentsStudy group –
E. Ladas RD MS, D. Hughes BA, S. Sands PsyD, D. Kroll PhD,
L. Vahdat MD, O. Bessmertny PharmD, M. Weiner MD,
K. Kelly MD, J. Glade Bender MDGCRC, Irving Center for Clinical Research at Columbia
UniversitySociety for Integrative Oncology
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