Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar)

Ranjana Advani, Hussain I. Saba, Martin S. Tallman, Jacob M. Rowe, Peter H. Wiernik, Joseph Ramek, Kathleen Dugan, Bert Lum, Jenny Villena, Eric Davis, Elisabeth M. Paietta, Manuel Litchman, Branimir I. Sikic, Peter L. Greenberg

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P- glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57% decrease in etoposide clearance (P = .001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P < .05). The doses of mitoxantrone and etoposide were substantially reduced to compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m2 mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C daily for 5 days. Overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36% (4 of 11) in patients with high PK parameters for either drug versus 5% (1 of 20) in those with lower PK parameters (P = .04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49%) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17% in cases lacking PSC-inhibitable efflux (P = .004). PSC- MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population.

Original languageEnglish (US)
Pages (from-to)787-795
Number of pages9
JournalBlood
Volume93
Issue number3
StatePublished - Feb 1 1999
Externally publishedYes

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Mitoxantrone
Chemotherapy
Multiple Drug Resistance
Etoposide
Combination Drug Therapy
Acute Myeloid Leukemia
Pharmacokinetics
Refractory materials
Modulators
P-Glycoprotein
Toxicity
Rhodamine 123
Therapeutics
Rhodamines
Oncology
Cytarabine
MDR Genes
Pharmaceutical Preparations
Drug Therapy
Granulocyte Precursor Cells

ASJC Scopus subject areas

  • Hematology

Cite this

Advani, R., Saba, H. I., Tallman, M. S., Rowe, J. M., Wiernik, P. H., Ramek, J., ... Greenberg, P. L. (1999). Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). Blood, 93(3), 787-795.

Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). / Advani, Ranjana; Saba, Hussain I.; Tallman, Martin S.; Rowe, Jacob M.; Wiernik, Peter H.; Ramek, Joseph; Dugan, Kathleen; Lum, Bert; Villena, Jenny; Davis, Eric; Paietta, Elisabeth M.; Litchman, Manuel; Sikic, Branimir I.; Greenberg, Peter L.

In: Blood, Vol. 93, No. 3, 01.02.1999, p. 787-795.

Research output: Contribution to journalArticle

Advani, R, Saba, HI, Tallman, MS, Rowe, JM, Wiernik, PH, Ramek, J, Dugan, K, Lum, B, Villena, J, Davis, E, Paietta, EM, Litchman, M, Sikic, BI & Greenberg, PL 1999, 'Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar)', Blood, vol. 93, no. 3, pp. 787-795.
Advani, Ranjana ; Saba, Hussain I. ; Tallman, Martin S. ; Rowe, Jacob M. ; Wiernik, Peter H. ; Ramek, Joseph ; Dugan, Kathleen ; Lum, Bert ; Villena, Jenny ; Davis, Eric ; Paietta, Elisabeth M. ; Litchman, Manuel ; Sikic, Branimir I. ; Greenberg, Peter L. / Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). In: Blood. 1999 ; Vol. 93, No. 3. pp. 787-795.
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abstract = "A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P- glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57{\%} decrease in etoposide clearance (P = .001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P < .05). The doses of mitoxantrone and etoposide were substantially reduced to compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m2 mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C daily for 5 days. Overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32{\%}) achieved complete remission, four achieved partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36{\%} (4 of 11) in patients with high PK parameters for either drug versus 5{\%} (1 of 20) in those with lower PK parameters (P = .04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49{\%}) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17{\%} in cases lacking PSC-inhibitable efflux (P = .004). PSC- MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population.",
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T1 - Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar)

AU - Advani, Ranjana

AU - Saba, Hussain I.

AU - Tallman, Martin S.

AU - Rowe, Jacob M.

AU - Wiernik, Peter H.

AU - Ramek, Joseph

AU - Dugan, Kathleen

AU - Lum, Bert

AU - Villena, Jenny

AU - Davis, Eric

AU - Paietta, Elisabeth M.

AU - Litchman, Manuel

AU - Sikic, Branimir I.

AU - Greenberg, Peter L.

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N2 - A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P- glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57% decrease in etoposide clearance (P = .001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P < .05). The doses of mitoxantrone and etoposide were substantially reduced to compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m2 mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C daily for 5 days. Overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36% (4 of 11) in patients with high PK parameters for either drug versus 5% (1 of 20) in those with lower PK parameters (P = .04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49%) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17% in cases lacking PSC-inhibitable efflux (P = .004). PSC- MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population.

AB - A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P- glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57% decrease in etoposide clearance (P = .001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P < .05). The doses of mitoxantrone and etoposide were substantially reduced to compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m2 mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C daily for 5 days. Overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36% (4 of 11) in patients with high PK parameters for either drug versus 5% (1 of 20) in those with lower PK parameters (P = .04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49%) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17% in cases lacking PSC-inhibitable efflux (P = .004). PSC- MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population.

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