Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan

A phase I study

Gordon L. Phillips, B. Meisenberg, D. E. Reece, V. R. Adams, A. Badros, J. Brunner, R. Fenton, J. Filicko, D. Grosso, G. A. Hale, D. S. Howard, V. P. Johnson, A. Kniska, K. W. Marshall, R. Nath, Elizabeth Cecile Reed, A. P. Rapoport, N. Takebe, D. H. Vesole, J. L. Wagner & 1 others N. Flomenberg

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

This study was conducted to define a new maximum tolerated dose and the dose-limiting toxicity (DLT) of melphalan and autologous hematopoietic stem cell transplantation (AHSCT) when used with the cytoprotective agent amifostine. Fifty-eight patients with various types of malignancy who were ineligible for higher-priority AHSCT protocols were entered on a phase I study of escalating doses of melphalan beginning at 220 mg/m2 and advancing by 20 mg/m2 increments in planned cohorts of 4 to 8 patients until severe regimen-related toxicity (RRT) was encountered. In all patients, amifostine 740 mg/m2 was given on 2 occasions before the first melphalan dose (ie, 24 hours before and again 15 minutes before). AHSCT was given 24 hours after the first melphalan dose. Melphalan was given in doses up to and including 300 mg/m2. Hematologic depression was profound, although it was rapidly and equally reversible at all melphalan doses. Although mucosal RRT was substantial, it was not the DLT, and some patients given the highest melphalan doses (ie, 300 mg/m2) did not develop mucosal RRT. The DLT was not clearly defined. Cardiac toxicity in the form of atrial fibrillation occurred in 3 of 36 patients treated with melphalan doses ≥280 mg/m2 and was deemed fatal in 1 patient given melphalan 300 mg/m2. (Another patient with a known cardiomyopathy was given melphalan 220 mg/m2 and died as a result of heart failure but did not have atrial fibrillation.) Another patient given melphalan 300 mg/m2 died of hepatic necrosis. The maximum tolerated dose of melphalan in this setting was thus considered to be 280 mg/m2, and 27 patients were given this dose without severe RRT. Moreover, 38 patients were evaluable for delayed toxicity related to RRT; none was noted. Tumor responses have been noted at all melphalan doses and in all diagnostic groups, and 21 patients are alive at median day +1121 (range, day +136 to day +1923), including 16 without evidence of disease progression at median day +1075 (range, day +509 to day +1638). Amifostine and AHSCT permit the safe use of melphalan 280 mg/m2, an apparent increase over the dose of melphalan that can be safely administered with AHSCT but without amifostine. Further studies are needed not only to confirm these findings, but also to define the antitumor efficacy of this regimen. Finally, it may be possible to evaluate additional methods of further dose escalation of melphalan in this setting.

Original languageEnglish (US)
Pages (from-to)473-483
Number of pages11
JournalBiology of Blood and Marrow Transplantation
Volume10
Issue number7
DOIs
StatePublished - Jul 1 2004

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Amifostine
Melphalan
Hematopoietic Stem Cells
Hematopoietic Stem Cell Transplantation
Maximum Tolerated Dose
Atrial Fibrillation

Keywords

  • Amifostine
  • Autologous hematopoietic stem cell transplantation
  • Escalating-dose melphalan
  • Regimen-related toxicity

ASJC Scopus subject areas

  • Hematology
  • Transplantation

Cite this

Phillips, G. L., Meisenberg, B., Reece, D. E., Adams, V. R., Badros, A., Brunner, J., ... Flomenberg, N. (2004). Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan: A phase I study. Biology of Blood and Marrow Transplantation, 10(7), 473-483. https://doi.org/10.1016/j.bbmt.2004.03.001

Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan : A phase I study. / Phillips, Gordon L.; Meisenberg, B.; Reece, D. E.; Adams, V. R.; Badros, A.; Brunner, J.; Fenton, R.; Filicko, J.; Grosso, D.; Hale, G. A.; Howard, D. S.; Johnson, V. P.; Kniska, A.; Marshall, K. W.; Nath, R.; Reed, Elizabeth Cecile; Rapoport, A. P.; Takebe, N.; Vesole, D. H.; Wagner, J. L.; Flomenberg, N.

In: Biology of Blood and Marrow Transplantation, Vol. 10, No. 7, 01.07.2004, p. 473-483.

Research output: Contribution to journalArticle

Phillips, GL, Meisenberg, B, Reece, DE, Adams, VR, Badros, A, Brunner, J, Fenton, R, Filicko, J, Grosso, D, Hale, GA, Howard, DS, Johnson, VP, Kniska, A, Marshall, KW, Nath, R, Reed, EC, Rapoport, AP, Takebe, N, Vesole, DH, Wagner, JL & Flomenberg, N 2004, 'Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan: A phase I study', Biology of Blood and Marrow Transplantation, vol. 10, no. 7, pp. 473-483. https://doi.org/10.1016/j.bbmt.2004.03.001
Phillips, Gordon L. ; Meisenberg, B. ; Reece, D. E. ; Adams, V. R. ; Badros, A. ; Brunner, J. ; Fenton, R. ; Filicko, J. ; Grosso, D. ; Hale, G. A. ; Howard, D. S. ; Johnson, V. P. ; Kniska, A. ; Marshall, K. W. ; Nath, R. ; Reed, Elizabeth Cecile ; Rapoport, A. P. ; Takebe, N. ; Vesole, D. H. ; Wagner, J. L. ; Flomenberg, N. / Amifostine and autologous hematopoietic stem cell support of escalating-dose melphalan : A phase I study. In: Biology of Blood and Marrow Transplantation. 2004 ; Vol. 10, No. 7. pp. 473-483.
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AU - Phillips, Gordon L.

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AU - Badros, A.

AU - Brunner, J.

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AU - Reed, Elizabeth Cecile

AU - Rapoport, A. P.

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N2 - This study was conducted to define a new maximum tolerated dose and the dose-limiting toxicity (DLT) of melphalan and autologous hematopoietic stem cell transplantation (AHSCT) when used with the cytoprotective agent amifostine. Fifty-eight patients with various types of malignancy who were ineligible for higher-priority AHSCT protocols were entered on a phase I study of escalating doses of melphalan beginning at 220 mg/m2 and advancing by 20 mg/m2 increments in planned cohorts of 4 to 8 patients until severe regimen-related toxicity (RRT) was encountered. In all patients, amifostine 740 mg/m2 was given on 2 occasions before the first melphalan dose (ie, 24 hours before and again 15 minutes before). AHSCT was given 24 hours after the first melphalan dose. Melphalan was given in doses up to and including 300 mg/m2. Hematologic depression was profound, although it was rapidly and equally reversible at all melphalan doses. Although mucosal RRT was substantial, it was not the DLT, and some patients given the highest melphalan doses (ie, 300 mg/m2) did not develop mucosal RRT. The DLT was not clearly defined. Cardiac toxicity in the form of atrial fibrillation occurred in 3 of 36 patients treated with melphalan doses ≥280 mg/m2 and was deemed fatal in 1 patient given melphalan 300 mg/m2. (Another patient with a known cardiomyopathy was given melphalan 220 mg/m2 and died as a result of heart failure but did not have atrial fibrillation.) Another patient given melphalan 300 mg/m2 died of hepatic necrosis. The maximum tolerated dose of melphalan in this setting was thus considered to be 280 mg/m2, and 27 patients were given this dose without severe RRT. Moreover, 38 patients were evaluable for delayed toxicity related to RRT; none was noted. Tumor responses have been noted at all melphalan doses and in all diagnostic groups, and 21 patients are alive at median day +1121 (range, day +136 to day +1923), including 16 without evidence of disease progression at median day +1075 (range, day +509 to day +1638). Amifostine and AHSCT permit the safe use of melphalan 280 mg/m2, an apparent increase over the dose of melphalan that can be safely administered with AHSCT but without amifostine. Further studies are needed not only to confirm these findings, but also to define the antitumor efficacy of this regimen. Finally, it may be possible to evaluate additional methods of further dose escalation of melphalan in this setting.

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