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Phase I Pharmacokinetic and Pharmacodynamic Study of Temozolomide in Pediatric Patients With Refractory or Recurrent Leukemia: A Children's Oncology Group Study

Terzah M. Horton, Patrick A. Thompson, Stacey L. Berg, Peter C. Adamson, Ashish M. Ingle, M. Eileen Dolan, Shannon M. Delaney, Madhuri Hedge, Heidi L. Weiss, Meng-Fen Wu, Susan M. Blaney

From the Texas Children's Cancer Center/Baylor College of Medicine; Diagnostic Sequencing Laboratory, Medical Genetics Laboratories, and Breast Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX; Children's Hospital of Philadelphia, Philadelphia, PA; Children's Oncology Group Operations Center, Arcadia, CA; and Section of Hematology-Oncology, Cancer Research Center and Committee on Clinical Pharmacology, The University of Chicago, Chicago, IL

Address reprint requests to Terzah M. Horton, MD, PhD, 6621 Fannin, MC 3-3320, Baylor College of Medicine, Houston, TX 77030; e-mail: tmhorton{at}txccc.org

Purpose To determine the tolerability, pharmacokinetics, and mechanisms of temozolomide resistance in children with relapsed or refractory leukemia.

Patients and Methods Cohorts of three to six patients received 200 or 260 mg/m²/d of temozolomide by mouth daily for 5 days every 28 days. Toxicities, clinical response, and pharmacokinetics were evaluated. Pretreatment leukemia cell O⁶-methylguanine–DNA methyltransferase (MGMT) activity, tumor and plasma MGMT promoter methylation, and microsatellite instability (MSI) were examined in 14 of 16 study patients and in tissue bank samples from children with acute leukemia not treated with temozolomide (MGMT, n = 67; MSI, n = 65).

Results Sixteen patients (nine female, seven male; acute lymphoblastic leukemia [ALL], n = 8; acute myeloid leukemia [AML], n = 8), median age 11 years (range, 1 to 19 years), received either 200 mg/m²/d (nine enrolled, three assessable for toxicity) or 260 mg/m²/d (seven enrolled, three assessable for toxicity) of temozolomide. Temozolomide was well tolerated and no dose-limiting toxicities occurred. The mean clearance of temozolomide was 107 mL/min/m², with a volume of distribution of 20 L/m² and half-life of 109 minutes. MGMT activity in leukemia cells was quite variable and was highest in patients with relapsed ALL. Only one patient had MSI. Two patients had a partial response. Both of these patients had no detectable MGMT activity; both also had methylated MGMT promoters and were MSI stable.

Conclusion Temozolomide was well tolerated at doses as high as 260 mg/m²/d for 5 days in children with relapsed or refractory leukemia. Increased MGMT activity may account for the temozolomide resistance in children with relapsed leukemia. Leukemia cell MGMT activity was higher in pediatric ALL than AML (P < .0001).

Supported by National Cancer Institute Grants No. UO1-CA97452 (C.O.G.), U01CA63187 (University of Chicago Cancer Research Center [UCCRC]), K12CA90433 (T.M.H.), The Lady Tata Memorial Fund (T.M.H.), the Scott Carter National Childhood Cancer Foundation Research Fellowship (T.M.H.). Pharmacologic studies were supported by the UCCRC Pharmacology Core Facility (http://pharmacology.bsd.uchicago.edu/) through the UCCRC Cancer Center Support Grant, P30 CA14599.

Presented in abstract form at the American Society of Hematology Meeting, San Diego, CA, December 10-15, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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