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Amie Davé November 16, 2007 Columbia College of Physicians and Surgeons

The effects of glutamine on vincristine-induced neuropathy in pediatric patients with cancer - a pilot study . Amie Davé November 16, 2007 Columbia College of Physicians and Surgeons Morgan Stanley Children’s Hospital of New York- Presbyterian New York University School of Medicine.

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Amie Davé November 16, 2007 Columbia College of Physicians and Surgeons

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  1. The effects of glutamine on vincristine-induced neuropathy in pediatric patients with cancer- a pilot study Amie Davé November 16, 2007 Columbia College of Physicians and Surgeons Morgan Stanley Children’s Hospital of New York- Presbyterian New York University School of Medicine

  2. Vincristine in Cancer Therapy • Vinca-alkaloid derived from the periwinkle plant • Integral 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 death • Interfere with many biochemical processes: amino acid uptake, inhibition of protein, DNA, & RNA synthesis, disrupts lipid & glucose metabolism

  3. Vincristine-Induced Neuropathy • Neurotoxicity is the dose-limiting toxicity of VCR therapy • Manifests as a sensory and/or motor neuropathy • Presentation 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

  4. Glutamine • Neutral non-essential amino acid, frequent use as a nutritional supplement • Glutamine depletion over time in cancer patients • May have a promising role in prophylaxis against VCR-induced neuropathy • Proposed 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

  5. 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 • Inclusion • Ages 5 to 21 years • Ability to complete baseline assessment • Diagnosis of leukemia or solid tumors and expected to receive ≥ 15 mg/m2 of VCR over 30 weeks • Exclusion • Primary CNS tumors or CNS metastases • Recurrent 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

  6. Study Instruments Symbol Digits Test Purdue Pegboard Test Hand Dynamometer Grip Strength

  7. Study Design • Neurological Assessments • Clinical exam • Purdue Pegboard Test • Symbol Digits Test • Grip Strength Test • Blood Collection • Serum NGF • Serum glutamine • Baseline, Day 0, 21, & 42 Baseline • Double-blind, randomized, placebo-controlled trial Neurological Status evaluated every 3 weeks • 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 Meet criteria  Randomization Glutamine Placebo Day 0 Day 0 Day 21 - discontinue supplement Day 21 Day 21 Glutamine dose6 g/m2 (max of 10 g/dose) BID Day 42 Day 42

  8. In vitro testing David J. Kroll, Ph.D. Senior Research PharmacologistResearch Triangle Park, NC • Physiologic levels of glutamine: 500 – 600 µM • CCRF-CEM human T-cell leukemia cells • The effects of 0.5, 2, 5, and 10 mM of glutamine on • cell cycle distribution • cellular growth rate • sensitivity to vincristine cytotoxicity • sensitivity to L-asparaginasecytotoxicity

  9. Results – In vitro testing

  10. Results – In vitro testing • No effect of glutamine on cell cycle distribution

  11. Results – In vitro testing • No effect of glutamine on vincristine sensitivity in CCRF-CEM cells

  12. Results – In vitro testing

  13. Clinical Trial Demographics • 23 patients, 3 removed, 2 on observation • Ages 5 – 19 years • Mean 9.9, Median 8.5 • 10 males, 8 females • Diagnosis • ALL – 16 • Rhabdomyosarcoma – 2 • Ewings sarcoma – 2 • Wilms tumor – 2 • Hodgkin’s Disease – 2

  14. Results – Randomization • Criteria for randomization met in first 18 of 18 patients • Criteria met by • Clinical exam – 5 patients • Neuropsych. Testing – 6 patients • Both – 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

  15. Results – Neuropsych. Testing • Potential practice effect with Symbol Digits test

  16. 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 randomization • Among six patients that received 6 mg/m2 ± 0.5, dose intensity varied from 2.5 to 5.8 mg/m2/28-day interval

  17. Results – Serum glutamine levels • No 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)

  18. Results – Serum glutamine levels • No significant differences between ALL and other diseases

  19. 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

  20. 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

  21. Acknowledgments • Study group – E. Ladas RD MS, D. Hughes BA, S. Sands PsyD, D. Kroll PhD, L. Vahdat MD, O. BessmertnyPharmD, M. Weiner MD, K. Kelly MD, J. Glade Bender MD • GCRC, Irving Center for Clinical Research at Columbia University • Society for Integrative Oncology

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