Stimulation of Megakaryocyte and Platelet Production by a Single Dose of Recombinant Human Thrombopoietin in Patients with Cancer

  1. Saroj Vadhan-Raj, MD;
  2. Lesley J. Murray, PhD;
  3. Carlos Bueso-Ramos, MD;
  4. Shreyaskumar Patel, MD;
  5. Saraswati P. Reddy, MD;
  6. William K. Hoots, MD;
  7. Taren Johnston, RN;
  8. Nicholas E. Papadopolous, MD;
  9. Walter N. Hittelman, PhD;
  10. Dennis A. Johnston, PhD;
  11. Timothy A. Yang, BA;
  12. Virginia E. Paton, PharmD;
  13. Robert L. Cohen, MD;
  14. Susan D. Hellmann, MD;
  15. Robert S. Benjamin, MD; and
  16. Hal E. Broxmeyer, PhD
  1. From The University of Texas M.D. Anderson Cancer Center, Houston, Texas; SyStemix, Inc., San Francisco, California; Genentech, Inc., South San Francisco, California; and Indiana University School of Medicine, Indianapolis, Indiana. Acknowledgments: The authors thank Duane Bloedow, PhD, and Tauri Senn for their help in pharmacokinetics analysis; Yang Huh, MD, for immunophenotypic analysis; Karin Luens for ploidy analysis; Debbie Sayre and Nancy Hague for technical assistance; and Zenaida Silva for manuscript preparation. Grant Support: In part by R01 HL56416, R01 HL54037, and P01 HL53586 from the National Heart, Lung, and Blood Institute and by a research grant from Genentech, Inc. (South San Francisco, California). Requests for Reprints: Saroj Vadhan-Raj, MD, Department of Bioimmunotherapy, Box 002, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Current Author Addresses: Drs. Vadhan-Raj and Reddy and Ms. Johnston: Department of Bioimmunotherapy, Box 002, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.

    Abstract

    Background: Thrombocytopenia is frequently encountered in patients with cancer. It is associated with an increased risk for clinically important bleeding episodes, which increases the demand for platelet transfusion.

    Objective: To assess hematopoietic response to and clinical tolerance of recombinant human thrombopoietin, a recently cloned novel cytokine.

    Design: Phase I and II clinical cohort study.

    Setting: The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

    Patients: 12 patients with sarcoma who had high risk for severe chemotherapy-induced thrombocytopenia.

    Intervention: A single intravenous dose of thrombopoietin (0.3 to 2.4 µg/kg of body weight) 3 weeks before chemotherapy.

    Measurements: Peripheral blood and bone marrow evaluation before and after thrombopoietin administration.

    Results: A single dose of thrombopoietin was associated with an increase in platelet counts (mean increase from baseline, 61% to 213%; P = 0.002) in a dose-related manner. This increase began by day 4 in most patients and peaked on a median of day 12. This sustained response was associated with a prolonged serum thrombopoietin half life (20 to 30 hours). The platelets appeared morphologically normal and showed normal aggregation in response to various agonists. Platelet response was accompanied by a dose-related increase in bone marrow megakaryocytes (as much as 4-fold); the expansion of the bone marrow progenitors of myeloid, erythroid, multipotential, and megakaryocytic lineages; and the marked mobilization of progenitors (maximum, 5.7-fold to 10-fold) of multiple cell lineages in the peripheral blood. Treatment was well tolerated, and no serious adverse events occurred.

    Conclusions: Thrombopoietin, administered as a single dose, is a potent stimulus for prolonged platelet production in humans. It merits further evaluation for the prevention and treatment of thrombocytopenia.

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    1. Ann Intern Med May 1, 1997 vol. 126 no. 9 673-681
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