Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1997;76(6):797–804. doi: 10.1038/bjc.1997.465

High-dose mitoxantrone with peripheral blood progenitor cell rescue: toxicity, pharmacokinetics and implications for dosage and schedule.

A Ballestrero 1, F Ferrando 1, A Garuti 1, P Basta 1, R Gonella 1, M Esposito 1, M O Vannozzi 1, G Sorice 1, D Friedman 1, M Puglisi 1, F Brema 1, G S Mela 1, M Sessarego 1, F Patrone 1
PMCID: PMC2228044  PMID: 9310249

Abstract

The optimal use of mitoxantrone (NOV) in the high-dose range requires elucidation of its maximum tolerated dose with peripheral blood progenitor cell (PBPC) support and the time interval needed between drug administration and PBPC reinfusion in order to avoid graft toxicity. The aims of this study were: (1) to verify the feasibility and haematological toxicity of escalating NOV up to 90 mg m(-2) with PBPC support; and (2) to verify the safeness of a short (96 h) interval between NOV administration and PBPC reinfusion. Three cohorts of ten patients with breast cancer (BC) or non-Hodgkin's lymphoma (NHL) received escalating doses of NOV, 60, 75 and 90 mg m(-2) plus melphalan (L-PAM), 140-180 mg m(-2), with PBPC rescue 96 h after NOV. Haematological toxicity was evaluated daily (WHO criteria). NOV plasma pharmacokinetics was also evaluated, as well as NOV cytotoxicity against PBPCs. Haematological recovery was rapid and complete at each NOV dose level without statistically significant differences, and there were no major toxicities. NOV plasma concentrations at the time of PBPC reinfusion were below the toxicity threshold against haemopoietic progenitors. It is concluded that, when adequately supported with PBPCs, NOV can be escalated up to 90 mg m(-2) with acceptable haematological toxicity. PBPCs can be safely reinfused as early as 96 h after NOV administration.

Full text

PDF
797

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alberts D. S., Peng Y. M., Leigh S., Davis T. P., Woodward D. L. Disposition of mitoxantrone in cancer patients. Cancer Res. 1985 Apr;45(4):1879–1884. [PubMed] [Google Scholar]
  2. Attal M., Canal P., Schlaifer D., Chatelut E., Dezeuze A., Huguet F., Payen C., Pris J., Laurent G. Escalating dose of mitoxantrone with high-dose cyclophosphamide, carmustine, and etoposide in patients with refractory lymphoma undergoing autologous bone marrow transplantation. J Clin Oncol. 1994 Jan;12(1):141–148. doi: 10.1200/JCO.1994.12.1.141. [DOI] [PubMed] [Google Scholar]
  3. Bowers C., Adkins D., Dunphy F., Harrison B., LeMaistre C. F., Spitzer G. Dose escalation of mitoxantrone given with thiotepa and autologous bone marrow transplantation for metastatic breast cancer. Bone Marrow Transplant. 1993 Nov;12(5):525–530. [PubMed] [Google Scholar]
  4. Canal P., Attal M., Chatelut E., Guichard S., Huguet F., Muller C., Schlaifer D., Laurent G., Houin G., Bugat R. Plasma and cellular pharmacokinetics of mitoxantrone in high-dose chemotherapeutic regimen for refractory lymphomas. Cancer Res. 1993 Oct 15;53(20):4850–4854. [PubMed] [Google Scholar]
  5. Ehninger G., Proksch B., Heinzel G., Woodward D. L. Clinical pharmacology of mitoxantrone. Cancer Treat Rep. 1986 Dec;70(12):1373–1378. [PubMed] [Google Scholar]
  6. Ellis E. D., Williams S. F., Moormeier J. A., Kaminer L. S., Bitran J. D. A phase I-II study of high-dose cyclophosphamide, thiotepa and escalating doses of mitoxantrone with autologous stem cell rescue in patients with refractory malignancies. Bone Marrow Transplant. 1990 Dec;6(6):439–442. [PubMed] [Google Scholar]
  7. Feldman E. J., Alberts D. S., Arlin Z., Ahmed T., Mittelman A., Baskind P., Peng Y. M., Baier M., Plezia P. Phase I clinical and pharmacokinetic evaluation of high-dose mitoxantrone in combination with cytarabine in patients with acute leukemia. J Clin Oncol. 1993 Oct;11(10):2002–2009. doi: 10.1200/JCO.1993.11.10.2002. [DOI] [PubMed] [Google Scholar]
  8. Fountzilas G., Ohnuma T., Rammos K., Mindich B., Holland J. F. Comparison of mitoxantrone and ametantrone in human acute myelocytic leukemia cells in culture and in bone marrow granulocyte-macrophage progenitor cells. Cancer Drug Deliv. 1986 Spring;3(2):93–100. doi: 10.1089/cdd.1986.3.93. [DOI] [PubMed] [Google Scholar]
  9. Freedman L. S., Workman P. When can the infusion period be safely ignored in the estimation of pharmacokinetic parameters of drugs in humans? Cancer Chemother Pharmacol. 1988;22(2):95–103. doi: 10.1007/BF00257304. [DOI] [PubMed] [Google Scholar]
  10. Frei E., 3rd, Canellos G. P. Dose: a critical factor in cancer chemotherapy. Am J Med. 1980 Oct;69(4):585–594. doi: 10.1016/0002-9343(80)90472-6. [DOI] [PubMed] [Google Scholar]
  11. Gabrilove J. L., Jakubowski A., Scher H., Sternberg C., Wong G., Grous J., Yagoda A., Fain K., Moore M. A., Clarkson B. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N Engl J Med. 1988 Jun 2;318(22):1414–1422. doi: 10.1056/NEJM198806023182202. [DOI] [PubMed] [Google Scholar]
  12. Gianni A. M., Bonadonna G. High dose chemo-radiotherapy for sensitive tumors: is sequential better than concurrent drug delivery? Eur J Cancer Clin Oncol. 1989 Jul;25(7):1027–1030. doi: 10.1016/0277-5379(89)90382-9. [DOI] [PubMed] [Google Scholar]
  13. Lemoli R. M., Gulati S. C. Effect of stem cell factor (c-kit ligand), granulocyte-macrophage colony stimulating factor and interleukin 3 on hematopoietic progenitors in human long-term bone marrow cultures. Stem Cells. 1993 Sep;11(5):435–444. doi: 10.1002/stem.5530110511. [DOI] [PubMed] [Google Scholar]
  14. Mulder P. O., Sleijfer D. T., Willemse P. H., de Vries E. G., Uges D. R., Mulder N. H. High-dose cyclophosphamide or melphalan with escalating doses of mitoxantrone and autologous bone marrow transplantation for refractory solid tumors. Cancer Res. 1989 Aug 15;49(16):4654–4658. [PubMed] [Google Scholar]
  15. Patrone F., Ballestrero A., Ferrando F., Brema F., Moraglio L., Valbonesi M., Basta P., Ghio R., Gobbi M., Sessarego M. Four-step high-dose sequential chemotherapy with double hematopoietic progenitor-cell rescue for metastatic breast cancer. J Clin Oncol. 1995 Apr;13(4):840–846. doi: 10.1200/JCO.1995.13.4.840. [DOI] [PubMed] [Google Scholar]
  16. Peng Y. M., Ormberg D., Alberts D. S., Davis T. P. Improved high-performance liquid chromatography of the new antineoplastic agents bisantrene and mitoxantrone. J Chromatogr. 1982 Dec 10;233:235–247. doi: 10.1016/s0378-4347(00)81750-8. [DOI] [PubMed] [Google Scholar]
  17. Richard B., Launay-Iliadis M. C., Iliadis A., Just-Landi S., Blaise D., Stoppa A. M., Viens P., Gaspard M. H., Maraninchi D., Cano J. P. Pharmacokinetics of mitoxantrone in cancer patients treated by high-dose chemotherapy and autologous bone marrow transplantation. Br J Cancer. 1992 Mar;65(3):399–404. doi: 10.1038/bjc.1992.81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Siena S., Bregni M., Bonsi L., Strippoli P., Peccatori F., Magni M., Di Nicola M., Bagnara G. P., Massimo Gianni A. Clinical implications of the heterogeneity of hematopoietic progenitors elicited in peripheral blood by anticancer therapy with cyclophosphamide and cytokine(s). Stem Cells. 1993 Jul;11 (Suppl 2):72–75. doi: 10.1002/stem.5530110812. [DOI] [PubMed] [Google Scholar]
  19. Siena S., Bregni M., Brando B., Belli N., Ravagnani F., Gandola L., Stern A. C., Lansdorp P. M., Bonadonna G., Gianni A. M. Flow cytometry for clinical estimation of circulating hematopoietic progenitors for autologous transplantation in cancer patients. Blood. 1991 Jan 15;77(2):400–409. [PubMed] [Google Scholar]
  20. Stiff P. J., McKenzie R. S., Alberts D. S., Sosman J. A., Dolan J. R., Rad N., McCloskey T. Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: high response rate for refractory ovarian carcinoma. J Clin Oncol. 1994 Jan;12(1):176–183. doi: 10.1200/JCO.1994.12.1.176. [DOI] [PubMed] [Google Scholar]
  21. Van Belle S. J., de Planque M. M., Smith I. E., van Oosterom A. T., Schoemaker T. J., Deneve W., McVie J. G. Pharmacokinetics of mitoxantrone in humans following single-agent infusion or intra-arterial injection therapy or combined-agent infusion therapy. Cancer Chemother Pharmacol. 1986;18(1):27–32. doi: 10.1007/BF00253059. [DOI] [PubMed] [Google Scholar]
  22. Von Hoff D. D., Clark G. M., Weiss G. R., Marshall M. H., Buchok J. B., Knight W. A., 3rd, LeMaistre C. F. Use of in vitro dose response effects to select antineoplastics for high-dose or regional administration regimens. J Clin Oncol. 1986 Dec;4(12):1827–1834. doi: 10.1200/JCO.1986.4.12.1827. [DOI] [PubMed] [Google Scholar]
  23. Wallerstein R., Jr, Spitzer G., Dunphy F., Huan S., Hortobagyi G., Yau J., Buzdar A., Holmes F., Theriault R., Ewer M. A phase II study of mitoxantrone, etoposide, and thiotepa with autologous marrow support for patients with relapsed breast cancer. J Clin Oncol. 1990 Nov;8(11):1782–1788. doi: 10.1200/JCO.1990.8.11.1782. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES