Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: Protection at the progenitor cell level

Saroj Vadhan-Raj, Hal E. Broxmeyer, Walter N. Hittelman, Nicholas E. Papadopoulos, Sant P. Chawla, Claudia Fenoglio, Scott Cooper, E. Stephen Buescher, Robert W. Frenck, Andrij Hollan, Raymond C. Perkins, Ronald K. Scheule, Jordan U. Gutterman, Philip Salem, Robert S. Benjamin

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Purpose: The purpose of this study was to optimize the dose, schedule, and timing of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) administration that would best abrogate myelosuppression in patients with sarcoma. Patients and Methods: Sarcoma patients who had experienced severe myelosuppression after chemotherapy with Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co, Evansville, IN), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dacarbazine ([CyADIC], cycle 1) were eligible. GM-CSF was administered during a 14-day period until 1 week before cycle 2 of CyADIC and was resumed 2 days after cycle 2 completion. The schedule subsequently was modified to allow the earlier administration of GM-CSF in which CyADIC was compressed from 5 days to 3 days, and GM-CSF was administered immediately after the discontinuation of CyADIC in cycle 2. To understand better the impact of GM-CSF on bone marrow stem cells, the proliferative status of bone marrow progenitors was examined during treatment. To evaluate the effects of GM-CSF on effector cells, select functions of mature myeloid cells were also examined. Results: In the seven patients who were treated on the initial schedule, GM-CSF enhanced the rate of neutrophil recovery; however, severe neutropenia was not abrogated. By using the modified schedule in 17 patients, GM-CSF significantly reduced both the degree and the duration of neutropenia and myeloid (neutrophils, eosinophils, and monocytes) leukopenia. The mean neutrophil and mature myeloid nadir counts were 100/mm3 and 280/mm3 in cycle 1 and 290/mm3 and 1,540/mm3 in cycle 2 (P < .01 and P < .001). The duration of severe neutropenia (neutrophil count < 500/mm3) and myeloid leukopenia (myeloid leukocyte count 1,000/mm3) were reduced from 6.2 and 6.8 days in cycle 1 to 2.8 and 1.4 days in cycle 2 (P < .001). While 16 of 17 patients experienced severe myeloid leukopenia (< 500/mm3) in cycle 1, only two of 17 experienced severe myeloid leukopenia in cycle 2 (P < .001). Overall, severe neutropenia was abrogated in seven patients, which made them eligible for dose-escalation of Adriamycin. The fraction of cycling progenitors increased threefold on GM-CSF and decreased dramatically below the baseline within 1 day of GM-CSF discontinuation. Conclusions: The modified schedule improved the beneficial effects of GM-CSF by enhancing myeloprotection and permitting dose-intensification of chemotherapy. The increased myeloid mass and quiescent progenitors at the initiation of chemotherapy suggest that GM-CSF might allow further chemotherapy dose-rate intensification by shortening the interval between courses.

Original languageEnglish
Pages (from-to)1266-1277
Number of pages12
JournalJournal of Clinical Oncology
Issue number8
StatePublished - 1992


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