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 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

Research output: Contribution to journalArticle

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Abstract

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 (US)
Pages (from-to)1266-1277
Number of pages12
JournalJournal of Clinical Oncology
Volume10
Issue number8
StatePublished - 1992
Externally publishedYes

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Granulocyte-Macrophage Colony-Stimulating Factor
Sarcoma
Stem Cells
Drug Therapy
Leukopenia
Appointments and Schedules
Neutropenia
Neutrophils
Doxorubicin
Cyclophosphamide
Dacarbazine
Myeloid Cells
Leukocyte Count
Eosinophils
Bone Marrow Cells
Monocytes
Bone Marrow

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma : Protection at the progenitor cell level. / Vadhan-Raj, Saroj; Broxmeyer, Hal; Hittelman, Walter N.; Papadopoulos, Nicholas E.; Chawla, Sant P.; Fenoglio, Claudia; Cooper, Scott; Stephen Buescher, E.; Frenck, Robert W.; Hollan, Andrij; Perkins, Raymond C.; Scheule, Ronald K.; Gutterman, Jordan U.; Salem, Philip; Benjamin, Robert S.

In: Journal of Clinical Oncology, Vol. 10, No. 8, 1992, p. 1266-1277.

Research output: Contribution to journalArticle

Vadhan-Raj, S, Broxmeyer, H, Hittelman, WN, Papadopoulos, NE, Chawla, SP, Fenoglio, C, Cooper, S, Stephen Buescher, E, Frenck, RW, Hollan, A, Perkins, RC, Scheule, RK, Gutterman, JU, Salem, P & Benjamin, RS 1992, 'Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: Protection at the progenitor cell level', Journal of Clinical Oncology, vol. 10, no. 8, pp. 1266-1277.
Vadhan-Raj, Saroj ; Broxmeyer, Hal ; Hittelman, Walter N. ; Papadopoulos, Nicholas E. ; Chawla, Sant P. ; Fenoglio, Claudia ; Cooper, Scott ; Stephen Buescher, E. ; Frenck, Robert W. ; Hollan, Andrij ; Perkins, Raymond C. ; Scheule, Ronald K. ; Gutterman, Jordan U. ; Salem, Philip ; Benjamin, Robert S. / Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma : Protection at the progenitor cell level. In: Journal of Clinical Oncology. 1992 ; Vol. 10, No. 8. pp. 1266-1277.
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title = "Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: Protection at the progenitor cell level",
abstract = "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.",
author = "Saroj Vadhan-Raj and Hal Broxmeyer and Hittelman, {Walter N.} and Papadopoulos, {Nicholas E.} and Chawla, {Sant P.} and Claudia Fenoglio and Scott Cooper and {Stephen Buescher}, E. and Frenck, {Robert W.} and Andrij Hollan and Perkins, {Raymond C.} and Scheule, {Ronald K.} and Gutterman, {Jordan U.} and Philip Salem and Benjamin, {Robert S.}",
year = "1992",
language = "English (US)",
volume = "10",
pages = "1266--1277",
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TY - JOUR

T1 - Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma

T2 - Protection at the progenitor cell level

AU - Vadhan-Raj, Saroj

AU - Broxmeyer, Hal

AU - Hittelman, Walter N.

AU - Papadopoulos, Nicholas E.

AU - Chawla, Sant P.

AU - Fenoglio, Claudia

AU - Cooper, Scott

AU - Stephen Buescher, E.

AU - Frenck, Robert W.

AU - Hollan, Andrij

AU - Perkins, Raymond C.

AU - Scheule, Ronald K.

AU - Gutterman, Jordan U.

AU - Salem, Philip

AU - Benjamin, Robert S.

PY - 1992

Y1 - 1992

N2 - 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.

AB - 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.

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