Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC)

R. Advani, G. Visani, D. Milligan, H. Saba, M. Tallman, J. M. Rowe, P. H. Wiernik, J. Ramek, K. Dugan, B. Lum, J. Villena, E. Davis, Elisabeth M. Paietta, M. Litchman, A. Covelli, B. Sikic, P. Greenberg

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The failure of convenional chemotherapy in relapsed or refractory and other poor risk AML patients has been linked to expression of the multidrug resistance gene (mdr1) product P-glycoprotein (P-gp). PSC 833 is a non-competitive inhibitor of P-gp and has been shown in vitro and in vivo to restore sensitivity of resistant tumor cells to anticancer drugs (ACDs). Induction chemotherapy consisting of cytarabine (C) in combination with PSC 833 and escalating doses of mitoxantrone (M) and etoposide (E) over 5 or 6 days were tested in two phase I/II studies in poor prognosis AML. Overall, 59 patients were evaluated: their age ranged between 18 and 70 years. Fourteen patients had primary refractory disease, 25 had relapsed within 9 months from first complete remission (CR), 5 were in second relapse, 10 had secondary AML, and 4 had relapsed post-bone marrow transplantation. PSC 833 was given as a constant i.v. infusion at a rate of 10 mg/kg/24h for 5 or 6 days, depending on the duration of chemotherapy. In both studies a loading dose of 2 mg/kg of PSC 833 was given on day 1. In the 5-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.0 mg/m2/d, and E 40 mg/m2/d. In the 6-day regimen, the final study doses of the cytotoxic agents were C l g/m2/d, M 4.5 mg/m2/d and E 30 mg/m2/d. The combined efficacy results of both studies indicate that PSC-MEC is active in all treatment indications, complete remission being achieved in 2/5 (40%) second relapses, 8/25 (32%) early relapses, 3/10 (30%) secondary AML, 3/15 (20%) refractory patients and 1/4 (25%) post-BMT relapses. Based on historical controls, this observed overall CR rate (29%) is higher than expected in this high risk patient population. Our data indicate that, in refractory/relapsed AML patients, PSC-MEC regimens had encouraging antileukemic effects, is well tolerated, and has led to Phase III trials in this setting.

Original languageEnglish (US)
Pages (from-to)47-56
Number of pages10
JournalAdvances in Experimental Medicine and Biology
Volume457
StatePublished - 1999
Externally publishedYes

Fingerprint

Mitoxantrone
Cytarabine
Etoposide
Refractory materials
Chemotherapy
Cytotoxins
P-Glycoprotein
Recurrence
Therapeutics
MDR Genes
Tumors
Drug Therapy
Bone
Induction Chemotherapy
Genes
Cells
Bone Marrow Transplantation
valspodar
Pharmaceutical Preparations
Population

Keywords

  • Clinical trials
  • Multidrug resistance
  • P-glycoprotein
  • Refractory/relapsing AML

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Advani, R., Visani, G., Milligan, D., Saba, H., Tallman, M., Rowe, J. M., ... Greenberg, P. (1999). Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Advances in Experimental Medicine and Biology, 457, 47-56.

Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). / Advani, R.; Visani, G.; Milligan, D.; Saba, H.; Tallman, M.; Rowe, J. M.; Wiernik, P. H.; Ramek, J.; Dugan, K.; Lum, B.; Villena, J.; Davis, E.; Paietta, Elisabeth M.; Litchman, M.; Covelli, A.; Sikic, B.; Greenberg, P.

In: Advances in Experimental Medicine and Biology, Vol. 457, 1999, p. 47-56.

Research output: Contribution to journalArticle

Advani, R, Visani, G, Milligan, D, Saba, H, Tallman, M, Rowe, JM, Wiernik, PH, Ramek, J, Dugan, K, Lum, B, Villena, J, Davis, E, Paietta, EM, Litchman, M, Covelli, A, Sikic, B & Greenberg, P 1999, 'Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC)', Advances in Experimental Medicine and Biology, vol. 457, pp. 47-56.
Advani, R. ; Visani, G. ; Milligan, D. ; Saba, H. ; Tallman, M. ; Rowe, J. M. ; Wiernik, P. H. ; Ramek, J. ; Dugan, K. ; Lum, B. ; Villena, J. ; Davis, E. ; Paietta, Elisabeth M. ; Litchman, M. ; Covelli, A. ; Sikic, B. ; Greenberg, P. / Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). In: Advances in Experimental Medicine and Biology. 1999 ; Vol. 457. pp. 47-56.
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abstract = "The failure of convenional chemotherapy in relapsed or refractory and other poor risk AML patients has been linked to expression of the multidrug resistance gene (mdr1) product P-glycoprotein (P-gp). PSC 833 is a non-competitive inhibitor of P-gp and has been shown in vitro and in vivo to restore sensitivity of resistant tumor cells to anticancer drugs (ACDs). Induction chemotherapy consisting of cytarabine (C) in combination with PSC 833 and escalating doses of mitoxantrone (M) and etoposide (E) over 5 or 6 days were tested in two phase I/II studies in poor prognosis AML. Overall, 59 patients were evaluated: their age ranged between 18 and 70 years. Fourteen patients had primary refractory disease, 25 had relapsed within 9 months from first complete remission (CR), 5 were in second relapse, 10 had secondary AML, and 4 had relapsed post-bone marrow transplantation. PSC 833 was given as a constant i.v. infusion at a rate of 10 mg/kg/24h for 5 or 6 days, depending on the duration of chemotherapy. In both studies a loading dose of 2 mg/kg of PSC 833 was given on day 1. In the 5-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.0 mg/m2/d, and E 40 mg/m2/d. In the 6-day regimen, the final study doses of the cytotoxic agents were C l g/m2/d, M 4.5 mg/m2/d and E 30 mg/m2/d. The combined efficacy results of both studies indicate that PSC-MEC is active in all treatment indications, complete remission being achieved in 2/5 (40{\%}) second relapses, 8/25 (32{\%}) early relapses, 3/10 (30{\%}) secondary AML, 3/15 (20{\%}) refractory patients and 1/4 (25{\%}) post-BMT relapses. Based on historical controls, this observed overall CR rate (29{\%}) is higher than expected in this high risk patient population. Our data indicate that, in refractory/relapsed AML patients, PSC-MEC regimens had encouraging antileukemic effects, is well tolerated, and has led to Phase III trials in this setting.",
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T1 - Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC)

AU - Advani, R.

AU - Visani, G.

AU - Milligan, D.

AU - Saba, H.

AU - Tallman, M.

AU - Rowe, J. M.

AU - Wiernik, P. H.

AU - Ramek, J.

AU - Dugan, K.

AU - Lum, B.

AU - Villena, J.

AU - Davis, E.

AU - Paietta, Elisabeth M.

AU - Litchman, M.

AU - Covelli, A.

AU - Sikic, B.

AU - Greenberg, P.

PY - 1999

Y1 - 1999

N2 - The failure of convenional chemotherapy in relapsed or refractory and other poor risk AML patients has been linked to expression of the multidrug resistance gene (mdr1) product P-glycoprotein (P-gp). PSC 833 is a non-competitive inhibitor of P-gp and has been shown in vitro and in vivo to restore sensitivity of resistant tumor cells to anticancer drugs (ACDs). Induction chemotherapy consisting of cytarabine (C) in combination with PSC 833 and escalating doses of mitoxantrone (M) and etoposide (E) over 5 or 6 days were tested in two phase I/II studies in poor prognosis AML. Overall, 59 patients were evaluated: their age ranged between 18 and 70 years. Fourteen patients had primary refractory disease, 25 had relapsed within 9 months from first complete remission (CR), 5 were in second relapse, 10 had secondary AML, and 4 had relapsed post-bone marrow transplantation. PSC 833 was given as a constant i.v. infusion at a rate of 10 mg/kg/24h for 5 or 6 days, depending on the duration of chemotherapy. In both studies a loading dose of 2 mg/kg of PSC 833 was given on day 1. In the 5-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.0 mg/m2/d, and E 40 mg/m2/d. In the 6-day regimen, the final study doses of the cytotoxic agents were C l g/m2/d, M 4.5 mg/m2/d and E 30 mg/m2/d. The combined efficacy results of both studies indicate that PSC-MEC is active in all treatment indications, complete remission being achieved in 2/5 (40%) second relapses, 8/25 (32%) early relapses, 3/10 (30%) secondary AML, 3/15 (20%) refractory patients and 1/4 (25%) post-BMT relapses. Based on historical controls, this observed overall CR rate (29%) is higher than expected in this high risk patient population. Our data indicate that, in refractory/relapsed AML patients, PSC-MEC regimens had encouraging antileukemic effects, is well tolerated, and has led to Phase III trials in this setting.

AB - The failure of convenional chemotherapy in relapsed or refractory and other poor risk AML patients has been linked to expression of the multidrug resistance gene (mdr1) product P-glycoprotein (P-gp). PSC 833 is a non-competitive inhibitor of P-gp and has been shown in vitro and in vivo to restore sensitivity of resistant tumor cells to anticancer drugs (ACDs). Induction chemotherapy consisting of cytarabine (C) in combination with PSC 833 and escalating doses of mitoxantrone (M) and etoposide (E) over 5 or 6 days were tested in two phase I/II studies in poor prognosis AML. Overall, 59 patients were evaluated: their age ranged between 18 and 70 years. Fourteen patients had primary refractory disease, 25 had relapsed within 9 months from first complete remission (CR), 5 were in second relapse, 10 had secondary AML, and 4 had relapsed post-bone marrow transplantation. PSC 833 was given as a constant i.v. infusion at a rate of 10 mg/kg/24h for 5 or 6 days, depending on the duration of chemotherapy. In both studies a loading dose of 2 mg/kg of PSC 833 was given on day 1. In the 5-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.0 mg/m2/d, and E 40 mg/m2/d. In the 6-day regimen, the final study doses of the cytotoxic agents were C l g/m2/d, M 4.5 mg/m2/d and E 30 mg/m2/d. The combined efficacy results of both studies indicate that PSC-MEC is active in all treatment indications, complete remission being achieved in 2/5 (40%) second relapses, 8/25 (32%) early relapses, 3/10 (30%) secondary AML, 3/15 (20%) refractory patients and 1/4 (25%) post-BMT relapses. Based on historical controls, this observed overall CR rate (29%) is higher than expected in this high risk patient population. Our data indicate that, in refractory/relapsed AML patients, PSC-MEC regimens had encouraging antileukemic effects, is well tolerated, and has led to Phase III trials in this setting.

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