Annals of Hematology

, Volume 67, Issue 6, pp 267–276

Hematopoietic recovery following high-dose combined alkylating-agent chemotherapy and autologous bone marrow support in patients in phase-I clinical trials of colony-stimulating factors: G-CSF, GM-CSF, IL-1, IL-2, M-CSF

  • M. J. Laughlin
  • G. Kirkpatrick
  • N. Sabiston
  • W. Peters
  • J. Kurtzberg
Original Article

Summary

Hematopoietic recovery in 115 patients with metastatic breast cancer or metastatic melanoma, enrolled in phase-I studies of recombinant growth factors while undergoing treatment with high-dose chemotherapy with autologous bone marrow support, was examined with assays of bone marrow progenitor cells and peripheral blood progenitor cells, and by evaluation of peripheral blood counts. Groups of patients receiving hematopoietic cytokine support [with interleukin-1 (IL-1), interleukin-2 (IL-2), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or monocyte CSF (M-CSF)] post marrow infusion were compared with contemporaneous control patients not receiving growth factor support. Patients receiving GM-CSF demonstrated statistically significant increases in the growth of granulocyte/macrophage colony-forming units (CFU-GM) in the bone marrow and peripheral blood compared with control patients. The effect of GM-CSF was dose dependent in the early period post marrow infusion (day +6) with bone marrow CFU-GM colonies at doses 8–16 μg/kg/ day 34 times those measured in controls. Significant increases in bone marrow multipotential progenitor cells (CFU-GEMM) were seen in patients receiving GMCSF day + 21 post marrow infusion. Patients receiving IL-1 demonstrated significant increases in bone marrow CFU-GM at day +21, maximal at dosages of 24–32 ng/kg/day. There were no significant increases in burst forming unit-erythroid (BFU-E) among any study group. Patients receiving G-CSF had significantly increased absolute neutrophil counts (ANC) and total white blood cell counts (WBC) by day +11 post transplant compared with control patients. Patients receiving GM-CSF demonstrated significantly increased WBC (greater than 2000/mm3) at day +11 and ANC greater than 500/mm3 at day +16. Optimal dose of GCSF and GM-CSF to stimulate neutrophil recovery post transplant was 4–8 μg/kg/day and 8–16 μg/kg/day, respectively. Platelet recovery did not differ among the six study groups. These data demonstrate accelerated myeloid recovery after high-dose chemotherapy and autologous bone marrow support in patients receiving either G-CSF or GM-CSF. Moreover, GM-CSF and IL-1 stimulate myelopoiesis at the level of bone marrow CFU-GM, while G-CSF causes earlier neutrophil recovery peripherally.

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References

  1. 1.
    Brandt SJ, Peters WP, Atwater SK, et al (1988) Effect of recombinant human granulocyte-macrophage colony-stimulating factor on hematopoietic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation. N Engl J Med 318:869–876PubMedGoogle Scholar
  2. 2.
    Nemunaitis J, Rabinowe SN, Singer JW, et al (1991) Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer. N Engl J Med 324:1773–1778PubMedGoogle Scholar
  3. 3.
    Jones RB, Shpall EJ, Shogan J, et al (1990) The Duke AFM program: intensive induction chemotherapy for metastatic breast cancer. Cancer 66:431–436PubMedGoogle Scholar
  4. 4.
    Advani R, Chao NJ, Horning SJ, et al (1992) Granulocytemacrophage colony-stimulating factor (GM-CSF) as an adjunct to autologous hemopoietic stem-cell transplantation for lymphoma. Ann Intern Med 116:183–189PubMedGoogle Scholar
  5. 5.
    Asano S, Masaoka T, Takaku F (1991) Beneficial effect of recombinant human glycosylated granulocyte colony-stimulating factor in marrow-transplanted patients: results of multicenter phase II–III studies. Transplant Proc 23:1701–1703PubMedGoogle Scholar
  6. 6.
    Sheridan WP, Wolf M, Lusk J, et al (1989) Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet 2:891–895PubMedGoogle Scholar
  7. 7.
    Dexter TM (1989) Regulation of hemopoietic cell growth and development: experimental and clinical studies. Leukemia 3:469–474PubMedGoogle Scholar
  8. 8.
    Masaoka T, Motoyoshi K, Takaku F (1988) Administration of human urinary colony-stimulating factor after bone marrow transplantation. Bone Marrow Transplant 3:121–127PubMedGoogle Scholar
  9. 9.
    McNiece I, Andrews R, Stewart M, et al (1989) Action of interleukin-3, G-CSF, and GM-CSF on highly enriched human hematopoietic progenitor cells: synergistic interaction of GM-CSF plus G-CSF. Blood 74:110–114PubMedGoogle Scholar
  10. 10.
    Bot FJ, Van Eijk L, Schipper P, et al (1990) Synergistic effects between GM-CSF and G-CSF or M-CSF on highly enriched human marrow progenitor cells. Leukemia 4/5:325–328Google Scholar
  11. 11.
    Krumwieh D, Seiler FR (1989) In vivo effects of recombinant colony-stimulating factors on hematopoiesis in cynomolgus monkeys. Transplant Proc 21:2964–2987PubMedGoogle Scholar
  12. 12.
    Laver J, Abboud M, Gasparetto C, et al (1989) Effects of interleukin-1 on hematopoietic progenitors after myelosuppressive chemoradiotherapy. Biotherapy 1:293–300PubMedGoogle Scholar
  13. 13.
    Hebert ME, Greenberg ML, Chaffee S, et al (1991) Pharmacologie purging of malignant T cells from human bone marrow using 9-β-D-arabinofuranosylguanine. Transplant 52:634–640Google Scholar
  14. 14.
    Rosenberg SA, Lotze MT, Muul LM, et al (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316:889–897PubMedGoogle Scholar
  15. 15.
    West WH, Tauer KW, Yannelli KR, et al (1987) Constantinfusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316:898–905PubMedGoogle Scholar
  16. 16.
    Broxmeyer HE, Williams DE, Lu L, et al (1986) The suppressive influences of human tumor necrosis factors on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: synergism of tumor necrosis factor and interferon-gamma. J Immunol 136:4487–4495PubMedGoogle Scholar
  17. 17.
    Heslop HE, Gottlieb DJ, Bianchi ACM, et al (1989) In vivo induction of gamma Interferon and tumour necrosis factor by interleukin 2 infusion following intensive chemotherapy or autologous marrow transplantation. Blood 74:1374–1380PubMedGoogle Scholar
  18. 18.
    Gottlieb DJ, Brenner MK, Heslop HE, et al (1989) A phase-I clinical trial of recombinant interleukin 2 following high-dose chemo-radiotherapy for haematological malignancy: applicability to the elimination of minimal residual disease. Br J Cancer 60:610–615PubMedGoogle Scholar
  19. 19.
    Biaise D, Stoppa AM, Olive D, et al (1991) Use of recombinant IL-2 (RU49637) after autologous bone marrow transplantation (BMT) in patients with hematological neoplasias: a phase-I study. Bone Marrow Transplant 7 [Suppl 2]: 146PubMedGoogle Scholar
  20. 20.
    Heslop HE, Duncombe AS, Reittie JE, et al (1991) Interleukin 2 infusion induces haemopoietic growth factors and modifies marrow regeneration after chemotherapy or autologous marrow transplantation. Br J Haematol 77:237–244PubMedGoogle Scholar
  21. 21.
    Bagby GC jr (1989) Interleukin-1 and hematopoiesis. Blood Rev 3:152–161PubMedGoogle Scholar
  22. 22.
    Crown J, Jakubowski A, Kemeny N, et al (1991) A phase-I trial of recombinant human interleukin-1 beta alone and in combination with myelosuppressive doses of 5-fluorouracil in patients with gastrointestinal cancer. Blood 78:1420–1427PubMedGoogle Scholar
  23. 23.
    Moore MAS, Stolfi RL, Martin DS (1990) Hematologie effects of interleukin-1 beta, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor in tumor-bearing mice treated with fluorouracil. J Natl Cancer Inst 82:1031–1037PubMedGoogle Scholar
  24. 24.
    Hogge DE, Cashman JD, Humphries RK, et al (1991) Differential and synergistic effects of human granulocyte-macrophage colony-stimulating factor and human granulocyte colony-stimulating factor on hematopoiesis in human long-term marrow cultures. Blood 77:493–499PubMedGoogle Scholar
  25. 25.
    Atkinson K, Maties C, Guiffre A, et al (1991) In vivo administration of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF, interleukin-1 (IL-1), and IL-4, alone and in combination, after allogeneic murine hematopoietic stem cell transplantation. Blood 77:1376–1382PubMedGoogle Scholar
  26. 26.
    Iscove NN, Yan XQ (1991) Precursors (pre-CFC multi) of multilineage hemopoietic colony-forming cells quantitated in vitro, uniqueness of IL-1 requirement, partial separation from pluripotential colony-forming cells, and correlation with long-term reconstituting cells in vivo. J Immunol 145:190–195Google Scholar
  27. 27.
    Peters WP, Atwater S, Kurtzberg J, et al (1989) The use of recombinant human granulocyte-macrophage colony-stimulating factor in autologous bone marrow transplantation. In: Bone marrow transplantation: current controversies. Alan R. Liss, New York, pp 595–606Google Scholar
  28. 28.
    Doyle MV, Lee MT, Fong S (1985) Comparison of the biological activities of human recombinant interleukin-2125 and native interleukin-2. J Biol Response Mod 4:96–109PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • M. J. Laughlin
    • 1
  • G. Kirkpatrick
    • 2
  • N. Sabiston
    • 2
  • W. Peters
    • 1
  • J. Kurtzberg
    • 2
  1. 1.Duke University Bone Marrow Transplant ProgramUSA
  2. 2.Pediatric Bone Marrow Research-LaboratoryDuke University Medical CenterDurhamUSA

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