Blut

, Volume 42, Issue 4, pp 209–220 | Cite as

High-dose nitrogen mustard (HN2) with autologous nonfrozen bone marrow transplantation in advanced malignant melanoma

A Phase I trial
  • D. W. Hartmann
  • W. A. Robinson
  • N. J. Morton
  • A. Mangalik
  • L. M. Glode
Original Works

Summary

In a Phase I trial patients with advanced malignant melanoma were treated with high-dose nitrogen mustard (HN2) and autologous bone marrow transplantation. Three patients were entered into the protocol. After procurement of 1.1–5.5×105 committed stem cells (CFU-C) per kg body wt, 33 mg/m2 of HN2 was administered i.v. as a bolus. Forty-eight hours later the noncryopreserved bone marrow was reinfused i.v. Side effects consisted of nausea, vomiting, anorexia, alopecia, phlebitis, hepatotoxicity, and neurotoxicity. Cardiotoxicity and hypocalcemia were encountered as unanticipated side effects not described so far by using lower dosages of HN2. Granulocytopenia of less than 1.0×109/l and thrombocytopenia of less than 50.0×109/l lasted for a mean of 10 and 8 days, respectively. Measureable disease present in two of three patients did not respond to the dose of HN2 used in this protocol. This study shows that hematologic recovery was shorter than previously reported in studies using HN2 without autologous bone marrow transplantation. The nonhematologic side effects of this dose of HN2, however, were severe and preclude the use of higher doses.

Key words

Malignant melanoma High-dose nitrogen mustard (HN2Autologous bone marrow transplantation 

Hochdosierte Mustargen-Therapie (HN2) mit autologer Knochenmarks-transplantation bei fortgeschrittenem malignem Melanom

Zusammenfassung

Wir berichten über eine Phase-I-Studie, in der drei Patienten mit fortgeschrittenem malignem Melanom mit Mustargen (HN2) in hoher Dosierung und autologer Knochenmarkstransplantation behandelt wurden. Nach der Entnahme von 1,1–5,5×105 determinierten Stammzellen (CFU-C) pro Kilogramm Körpergewicht wurden 33 mg/m2 HN2 i.v. injiziert. Achtundvierzig Stunden später wurde das Knochenmark transfundiert. Die Nebenwirkungen bestanden aus Erbrechen, übelkeit, Appetitlosigkeit, Haarausfall, Venenentzündung, Leber- und Nerventoxizität. Beeinträchtigung der Herzfunktion und Hypokalzämie waren unerwartete Nebenwirkungen, die bisher bei der üblichen Dosierung von HN2 nicht beschrieben worden sind. Granulopenie von weniger als 1,0×109/l dauerte 10 Tage, Thrombopenie von weniger als 50,0×109/l 8 Tage. Die me\baren Metastasen von zwei Patienten sprachen auf die Behandlung nicht an. Diese Studie zeigt anhand eines historischen Vergleichs, da\ die Erholung der Knochenmarksfunktion durch die Verwendung von autologem Knochenmark beschleunigt wurde, da\ aber die schweren, nichthämologischen Nebenwirkungen eine weitere Dosissteigerung von HN2 ausschlie\en.

Schlüsselwörter

malignes Melanom hochdosiertes Mustargen (HN2autologe Knochenmarkstransplantation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Appelbaum FR, Herzig GP, Ziegler JL, Graw RG, Levine AS, Deisseroth AB (1978) Successful engraftment of cryopreserved autologous bone marrow in patients with malignant melanoma. Blood 52: 85–95Google Scholar
  2. 2.
    Abrams RA, Deisseroth AB (1979) Prospects for accelerating hemopoietic recovery following myelosuppressive therapy by using autologous cryo-preserved hemopoietic stem cells collected solely from the peripheral blood. Exp Hematol [Suppl 5] 7: 107–115Google Scholar
  3. 3.
    Bierman HR Shimkin MB, Mettier SR Weaver J, Berry WC, Wise SP III (1949) Methyl-bis (beta-chloroethyl) amine in large doses in the treatment of neoplastic disease. Calif Med 71: 117–125Google Scholar
  4. 4.
    Black MM, Speer FD Stone ML (1959) Protective action of autologous marrow against nitrogen mustard toxicity. Ann Intern Med 51: 517–525Google Scholar
  5. 5.
    Burgess AW, Wilson EMA, Metcalf D (1977) Stimulation by human placental conditioned medium of hemopoietic colony formation by human marrow cells. Blood 49: 573–583Google Scholar
  6. 6.
    Clifford P, Clift RA, Duff JK (1961) Nitrogen mustard therapy combined with autologous marrow infusion. Lancet 1: 687–690Google Scholar
  7. 7.
    Comis RL (1976) DTIC (NSC 45388) in malignant melanoma: A perspective. Cancer Treat Rep 60: 165–176Google Scholar
  8. 8.
    Dameshek W, Weisfuse L, Stein T (1949) Nitrogen mustard therapy in Hodgkin's disease. Blood 4: 338–379Google Scholar
  9. 9.
    De Vita VT, Fisher RI (1976) Natural history of malignant melanoma as related to therapy. Cancer Treat Rep 60: 153–157Google Scholar
  10. 10.
    Entringer MA, Robinson WA, Kurnick JE (1977) Colony growth of normal human bone marrow in agar gel. Exp Hematol 5: 125–135 (1977)Google Scholar
  11. 11.
    Frei E III (1979) Antitumor agents-dose response curve. Clinical and experimental considerations. Exp Hematol [Suppl 5] 7: 262–264Google Scholar
  12. 12.
    Hartmann DW, Robinson WA, Mangalik A, Glode LM, Triebel F (1980) Unanticipated side effects from treatment with high dose nitrogen mustard in patients with malignant melanoma. Cancer Treat Rep (submitted)Google Scholar
  13. 13.
    Jacobson LO, Marks EK, Simmons EL, Gaston EO, Zirkle RE (1949) The effect of spleen on mortality following x-irradiation. J Lab Clin Med 34: 1538–1543Google Scholar
  14. 14.
    Keoffler HPH, Gale RP, Golde DW (1980) Myeloid colony forming cell kinetics in man. Exp Hematol 8: 271–277Google Scholar
  15. 15.
    Kolar V, Kadlecova D (1970) Treatment of malignant tumors with high doses of nitrogen mustard (TS 160) and/or high doses of ionizing radiation under the protection of autologous bone marrow. Neoplasma 17: 535–540Google Scholar
  16. 16.
    Kurnick JE, Robinson WA (1971) Colony growth of ‘human peripheral’ white blood cells in vitro. Blood 37: 136–141Google Scholar
  17. 17.
    Mangalik A, Robinson WA, Drebing C, Hartmann DW, Joshi JH (1979) Liquid storage of bone marrow. Exp Hematol [Suppl 5] 7: 76–94Google Scholar
  18. 18.
    Mangalik A, Robinson WA, Morton NJ (1979) Stem cell kinetics in humans: studies during autologous nonfrozen bone marrow transplantation. Exp Hematol [Suppl 5] 7: 188–199Google Scholar
  19. 19.
    McElwain TJ, Hedley DW, Gordon MY, Jarman M, Millar JL, Pritchard J (1979) High-dose melphalan and noncryopreserved autologous bone marrow treatment of malignant melanoma and neuroblastoma. Exp Hematol [Suppl 5] 7: 360–371Google Scholar
  20. 20.
    McFarland W, Granville NB, Dameshek W (1959) Autologous bone marrow infusion as an adjuvant in therapy of malignant disease. Blood 14: 503–521Google Scholar
  21. 21.
    Meyer LM, Fliedner TM, Cronkite EP (1964) Autologous bone marrow transfusion following chemotherapy. Ann NY Acad Sci 144: 499–509Google Scholar
  22. 22.
    Philips GL, Fay JW, Herzig GP, Napombeyara C, Wolff JN (1979) Intensive 1,3-bis (2- chloroethyl)-1-nitrosourea (BCNU) autologous bone marrow transplantation therapy of refractory cancer: A preliminary report. Exp Hematol [Suppl 5] 7: 372–383Google Scholar
  23. 23.
    Pike BL, Robinson WA (1970) Human bone marrow colony growth in agar gel. J Cell Physiol 76: 77–84Google Scholar
  24. 24.
    Skipper HE, Schabel Jr FM, Wilcox WS (1964) Experimental evaluation of potential anticancer agents. XII. On the criteria and kinetics associated with curability of experimental leukemia. Cancer Chemother Rep 35: 1–111Google Scholar
  25. 25.
    Smiley RK, Martin-Villar J, Belanger LF (1961) Effect of autologous bone marrow on the cytopenias induced by nitrogen mustard. Can MAJ 84: 1230–1234Google Scholar
  26. 26.
    Spitzer G, Dicke KA, Verma DS, Zander A, Litam J, Distefano A, Lanzotti V (1979) Highdose chemotherapy with autologous bone marrow transfusion. Exp Hematol [Suppl 5] 7: 38–53Google Scholar
  27. 27.
    Wells JR, Ho WG, Graze P, Sullivan A, Gale RP, Cline MI (1979) Isolation, cryopreservation and autotransplantation of human stem cells. Exp Hematol [Suppl 5] 7: 12–20Google Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • D. W. Hartmann
    • 1
  • W. A. Robinson
    • 1
  • N. J. Morton
    • 1
  • A. Mangalik
    • 1
  • L. M. Glode
    • 1
  1. 1.Department of Medicine, Division of Medical OncologyUniversity of Colorado Health Sciences CenterDenverUSA

Personalised recommendations