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Importance of Predosing of Recombinant Human Thrombopoietin to Reduce Chemotherapy-Induced Early Thrombocytopenia

Saroj Vadhan-Raj, Shreyaskumar Patel, Carlos Bueso-Ramos, Jody Folloder, Nicholas Papadopolous, Andrew Burgess, Lyle D. Broemeling, Hal E. Broxmeyer, Robert S. Benjamin

From the Departments of Bioimmunotherapy, Sarcoma Medical Oncology, Hematopathology, and Biostatistics, the University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Department of Microbiology and Immunology, the Walther Oncology Center and the Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN.

Address reprint requests to Saroj Vadhan-Raj, MD, Department of Bioimmunotherapy, Box 422, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: svadhanr{at}mail.mdanderson.org.

Purpose: Recombinant human thrombopoietin (rhTPO) increases platelets, and the peak response of rhTPO is delayed and is, therefore, not uniformly effective when administered after chemotherapy. The purpose of this study was to identify an effective schedule of rhTPO to best attenuate early thrombocytopenia.

Patients and Methods: Cohorts of six patients with sarcoma (66 assessable patients) were treated sequentially with doxorubicin and ifosfamide (AI), with rhTPO by a fixed dose and varying schedules being administered before and/or after chemotherapy in cycle 2 and subsequent cycles. Cycle 1 without rhTPO served as an internal control.

Results: AI causes cumulative thrombocytopenia. The platelet nadir in cycle 2 was higher than in cycle 1 (mean nadir ± SEM, 119 ± 12 x 10³/µL v 80 ± 7 x 10³/µL, respectively; P < .001) in 24 (80%) of the 30 patients (P < .001) in whom rhTPO (1.2 µg/kg) was administered starting from 5 days before chemotherapy (pre/postdoses, three/one or one/one) compared with only four (17%) of 24 patients given rhTPO by other schedules (pre/postdoses, two/two, one/three, zero/four, or four/zero) and none of 15 historical control patients. The need for platelet transfusions in four cycles was significantly lower (13 [11%] of 114 cycles, P < .001) in patients who received rhTPO from day -5 (pre/post doses, three/one or one/one) compared with patients who received rhTPO at later time points (28 [47%] of 60 cycles). Bone marrow megakaryocytes increased markedly (four-fold) before chemotherapy with predosing rhTPO and remained elevated (two-fold) after chemotherapy, which may explain the possible mechanism for response. One patient developed subclavian vein thrombosis, and no patients developed neutralizing antibodies to rhTPO.

Conclusion: These results demonstrate the importance of timing of rhTPO in relation to chemotherapy and indicate that, by optimizing the timing, only two doses of rhTPO (one before and one after chemotherapy) were required to significantly reduce the severity of chemotherapy-related early thrombocytopenia.

Supported in part by Public Health Service grant Nos. RO1 HL56416 and DK53674 from the National Institutes of Health, Bethesda, MD, various donors funds, and a research grant from Pharmacia Oncology, Peapack, NJ.

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