Cyclosporin A does not reverse clinical resistance to paclitaxel in patients with relapsed non-Hodgkin's lymphoma

A. H. Sarris, A. Younes, P. McLaughlin, D. Moore, F. Hagemeister, F. Swan, M. A. Rodriguez, J. Romaguera, L. North, P. Mansfield, David Callender, O. Mesina, F. Cabanillas

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Abstract

Purpose: Cyclosporin A has been shown to reverse paclitaxel resistance in vitro by inhibiting P-gp function. Therefore, we determined whether addition of cyclosporine to paclitaxel reversed clinical paclitaxel resistance in patients with non-Hodgkin's lymphoma (NHL). Patients and Methods: Patients with relapsed NHL were eligible if they had no intervening treatment after failure to respond to paclitaxel (200 mg/m2 over 3 hours), and if they had adequate marrow, renal, and hepatic function, no serious cardiac disease, no CNS involvement, and no antibodies to human immunodeficiency virus-1. A cyclosporin A bolus dose (5 mg/kg over 3 hours) was followed by intravenous infusion (15 mg/kg) over 24 hours. Six hours after the beginning of cyclosporin A, the immediately preceding paclitaxel dose was administered over 3 hours. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Response was assessed after two cycles, and those patients who achieved at least a partial response received a maximum of six courses. Results: All 26 patients entered were assessable for toxicity and 25 were assessable for response. One patient whose disease had progressed during paclitaxel treatment had a partial remission after the addition of cyclosporin A (response rate, 4%; 95% confidence interval, 1% to 20%). Disease progressed in 17 patients (71%) and did not respond in seven (25%). Serum cyclosporin A A levels measured at the time of initiation of paclitaxel infusion were greater than 2,000 ng/mL during 81% of cycles. Treatment toxicity included peripheral neuropathy in 57%, myalgia or arthralgia in 30%, neutropenia in 53%, neutropenic fever in 8%, and thrombocytopenia in 42% of patients. One patient with preexisting asthma had an acute bronchospasm during the first cycle and was removed from the study. There were no renal or hepatic toxicity and no infectious or hemorrhagic deaths. Conclusion: Cyclosporin A administered on this schedule did not reverse established clinical resistance to paclitaxel, which suggests that P-gp-mediated drug efflux is unlikely to be the only cause of paclitaxel resistance in this patient population.

Original languageEnglish (US)
Pages (from-to)233-239
Number of pages7
JournalJournal of Clinical Oncology
Volume14
Issue number1
StatePublished - Jan 1996
Externally publishedYes

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Paclitaxel
Non-Hodgkin's Lymphoma
Cyclosporine
Kidney
Diphenhydramine
Bronchial Spasm
Liver
Myalgia
Cimetidine
Arthralgia
Peripheral Nervous System Diseases
Neutropenia
Treatment Failure
Intravenous Infusions
Thrombocytopenia
Dexamethasone
HIV-1
Heart Diseases
Appointments and Schedules
Fever

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sarris, A. H., Younes, A., McLaughlin, P., Moore, D., Hagemeister, F., Swan, F., ... Cabanillas, F. (1996). Cyclosporin A does not reverse clinical resistance to paclitaxel in patients with relapsed non-Hodgkin's lymphoma. Journal of Clinical Oncology, 14(1), 233-239.

Cyclosporin A does not reverse clinical resistance to paclitaxel in patients with relapsed non-Hodgkin's lymphoma. / Sarris, A. H.; Younes, A.; McLaughlin, P.; Moore, D.; Hagemeister, F.; Swan, F.; Rodriguez, M. A.; Romaguera, J.; North, L.; Mansfield, P.; Callender, David; Mesina, O.; Cabanillas, F.

In: Journal of Clinical Oncology, Vol. 14, No. 1, 01.1996, p. 233-239.

Research output: Contribution to journalArticle

Sarris, AH, Younes, A, McLaughlin, P, Moore, D, Hagemeister, F, Swan, F, Rodriguez, MA, Romaguera, J, North, L, Mansfield, P, Callender, D, Mesina, O & Cabanillas, F 1996, 'Cyclosporin A does not reverse clinical resistance to paclitaxel in patients with relapsed non-Hodgkin's lymphoma', Journal of Clinical Oncology, vol. 14, no. 1, pp. 233-239.
Sarris AH, Younes A, McLaughlin P, Moore D, Hagemeister F, Swan F et al. Cyclosporin A does not reverse clinical resistance to paclitaxel in patients with relapsed non-Hodgkin's lymphoma. Journal of Clinical Oncology. 1996 Jan;14(1):233-239.
Sarris, A. H. ; Younes, A. ; McLaughlin, P. ; Moore, D. ; Hagemeister, F. ; Swan, F. ; Rodriguez, M. A. ; Romaguera, J. ; North, L. ; Mansfield, P. ; Callender, David ; Mesina, O. ; Cabanillas, F. / Cyclosporin A does not reverse clinical resistance to paclitaxel in patients with relapsed non-Hodgkin's lymphoma. In: Journal of Clinical Oncology. 1996 ; Vol. 14, No. 1. pp. 233-239.
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abstract = "Purpose: Cyclosporin A has been shown to reverse paclitaxel resistance in vitro by inhibiting P-gp function. Therefore, we determined whether addition of cyclosporine to paclitaxel reversed clinical paclitaxel resistance in patients with non-Hodgkin's lymphoma (NHL). Patients and Methods: Patients with relapsed NHL were eligible if they had no intervening treatment after failure to respond to paclitaxel (200 mg/m2 over 3 hours), and if they had adequate marrow, renal, and hepatic function, no serious cardiac disease, no CNS involvement, and no antibodies to human immunodeficiency virus-1. A cyclosporin A bolus dose (5 mg/kg over 3 hours) was followed by intravenous infusion (15 mg/kg) over 24 hours. Six hours after the beginning of cyclosporin A, the immediately preceding paclitaxel dose was administered over 3 hours. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Response was assessed after two cycles, and those patients who achieved at least a partial response received a maximum of six courses. Results: All 26 patients entered were assessable for toxicity and 25 were assessable for response. One patient whose disease had progressed during paclitaxel treatment had a partial remission after the addition of cyclosporin A (response rate, 4{\%}; 95{\%} confidence interval, 1{\%} to 20{\%}). Disease progressed in 17 patients (71{\%}) and did not respond in seven (25{\%}). Serum cyclosporin A A levels measured at the time of initiation of paclitaxel infusion were greater than 2,000 ng/mL during 81{\%} of cycles. Treatment toxicity included peripheral neuropathy in 57{\%}, myalgia or arthralgia in 30{\%}, neutropenia in 53{\%}, neutropenic fever in 8{\%}, and thrombocytopenia in 42{\%} of patients. One patient with preexisting asthma had an acute bronchospasm during the first cycle and was removed from the study. There were no renal or hepatic toxicity and no infectious or hemorrhagic deaths. Conclusion: Cyclosporin A administered on this schedule did not reverse established clinical resistance to paclitaxel, which suggests that P-gp-mediated drug efflux is unlikely to be the only cause of paclitaxel resistance in this patient population.",
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AU - Sarris, A. H.

AU - Younes, A.

AU - McLaughlin, P.

AU - Moore, D.

AU - Hagemeister, F.

AU - Swan, F.

AU - Rodriguez, M. A.

AU - Romaguera, J.

AU - North, L.

AU - Mansfield, P.

AU - Callender, David

AU - Mesina, O.

AU - Cabanillas, F.

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N2 - Purpose: Cyclosporin A has been shown to reverse paclitaxel resistance in vitro by inhibiting P-gp function. Therefore, we determined whether addition of cyclosporine to paclitaxel reversed clinical paclitaxel resistance in patients with non-Hodgkin's lymphoma (NHL). Patients and Methods: Patients with relapsed NHL were eligible if they had no intervening treatment after failure to respond to paclitaxel (200 mg/m2 over 3 hours), and if they had adequate marrow, renal, and hepatic function, no serious cardiac disease, no CNS involvement, and no antibodies to human immunodeficiency virus-1. A cyclosporin A bolus dose (5 mg/kg over 3 hours) was followed by intravenous infusion (15 mg/kg) over 24 hours. Six hours after the beginning of cyclosporin A, the immediately preceding paclitaxel dose was administered over 3 hours. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Response was assessed after two cycles, and those patients who achieved at least a partial response received a maximum of six courses. Results: All 26 patients entered were assessable for toxicity and 25 were assessable for response. One patient whose disease had progressed during paclitaxel treatment had a partial remission after the addition of cyclosporin A (response rate, 4%; 95% confidence interval, 1% to 20%). Disease progressed in 17 patients (71%) and did not respond in seven (25%). Serum cyclosporin A A levels measured at the time of initiation of paclitaxel infusion were greater than 2,000 ng/mL during 81% of cycles. Treatment toxicity included peripheral neuropathy in 57%, myalgia or arthralgia in 30%, neutropenia in 53%, neutropenic fever in 8%, and thrombocytopenia in 42% of patients. One patient with preexisting asthma had an acute bronchospasm during the first cycle and was removed from the study. There were no renal or hepatic toxicity and no infectious or hemorrhagic deaths. Conclusion: Cyclosporin A administered on this schedule did not reverse established clinical resistance to paclitaxel, which suggests that P-gp-mediated drug efflux is unlikely to be the only cause of paclitaxel resistance in this patient population.

AB - Purpose: Cyclosporin A has been shown to reverse paclitaxel resistance in vitro by inhibiting P-gp function. Therefore, we determined whether addition of cyclosporine to paclitaxel reversed clinical paclitaxel resistance in patients with non-Hodgkin's lymphoma (NHL). Patients and Methods: Patients with relapsed NHL were eligible if they had no intervening treatment after failure to respond to paclitaxel (200 mg/m2 over 3 hours), and if they had adequate marrow, renal, and hepatic function, no serious cardiac disease, no CNS involvement, and no antibodies to human immunodeficiency virus-1. A cyclosporin A bolus dose (5 mg/kg over 3 hours) was followed by intravenous infusion (15 mg/kg) over 24 hours. Six hours after the beginning of cyclosporin A, the immediately preceding paclitaxel dose was administered over 3 hours. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Response was assessed after two cycles, and those patients who achieved at least a partial response received a maximum of six courses. Results: All 26 patients entered were assessable for toxicity and 25 were assessable for response. One patient whose disease had progressed during paclitaxel treatment had a partial remission after the addition of cyclosporin A (response rate, 4%; 95% confidence interval, 1% to 20%). Disease progressed in 17 patients (71%) and did not respond in seven (25%). Serum cyclosporin A A levels measured at the time of initiation of paclitaxel infusion were greater than 2,000 ng/mL during 81% of cycles. Treatment toxicity included peripheral neuropathy in 57%, myalgia or arthralgia in 30%, neutropenia in 53%, neutropenic fever in 8%, and thrombocytopenia in 42% of patients. One patient with preexisting asthma had an acute bronchospasm during the first cycle and was removed from the study. There were no renal or hepatic toxicity and no infectious or hemorrhagic deaths. Conclusion: Cyclosporin A administered on this schedule did not reverse established clinical resistance to paclitaxel, which suggests that P-gp-mediated drug efflux is unlikely to be the only cause of paclitaxel resistance in this patient population.

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