High-dose celecoxib and metronomic "low-dose" cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin's lymphoma

Rena Buckstein, Robert S. Kerbel, Yuval Snaked, Rakesh Nayar, Cindy Foden, Ruth Turner, Christine R. Lee, Diane Taylor, Liying Zhang, Shan Man, Sylvain Baruchel, Diana Stempak, Francesco Bertolini, Michael Crump

Research output: Contribution to journalArticle

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Abstract

Purpose: Angiogenesis is increased in aggressive histology non-Hodgkin's lymphoma and may be a target with selective cyclooxygenase-2 inhibition and metronomic chemotherapy. Experimental Design: We assessed response, toxicity, and biomarkers of angiogenesis to low-dose cyclophosphamide (50 mg p.o. o.d.) and high-dose celecoxib (400 mg p.o. b.i.d.) in adult patients with relapsed or refractory aggressive non-Hodgkin's lymphoma in a multicenter phase II prospective study. Results: Thirty-two of 35 patients (median age, 62 years) are evaluable for response. Patients had primarily relapsed diffuse large B-cell lymphoma (63%) were heavily pretreated (median of three regimens) and high risk (79% international prognostic index, ≥2) and 34% were relapsed after autologous stem cell transplant. With a median follow-up of 8.4 months, the overall best response rate is 37% (2 complete clinical response/complete clinical response unconfirmed and 9 partial response), with 22% achieving stable disease. Median overall and progression-free survivals are 14.4 and 4.7 months, respectively. The median response duration was 8.2 months. The most common toxicity was skin rash (40%); myelosuppression and gastrointestinal side effects were uncommon. Three patients developed deep vein thromboses and two heavily pretreated patients developed treatment-related acute myelogenous leukemia or myelodysplasia after 3.7 and 12 months of therapy. Circulating endothelial cells and their precursors declined and remained low in responders, whereas plasma vascular endothelial growth factor trended to decline in responding patients but increase in nonresponders. Trough celecoxib levels achieved targeted "antiangiogenic" levels. Conclusions: Low-dose cyclophosphamide and high-dose celecoxib is well tolerated and active in pretreated aggressive non-Hodgkin's lymphoma. Close surveillance for arterial and venous thrombotic events is recommended. The decline in circulating endothelial cells and their precursors suggests that this combination may be working by inhibiting angiogenesis but should be validated in a larger patient sample.

Original languageEnglish
Pages (from-to)5190-5198
Number of pages9
JournalClinical Cancer Research
Volume12
Issue number17
DOIs
Publication statusPublished - Sep 1 2006

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Celecoxib
Non-Hodgkin's Lymphoma
Cyclophosphamide
Histology
Therapeutics
Endothelial Cells
Lymphoma, Large B-Cell, Diffuse
Cyclooxygenase 2
Exanthema
Acute Myeloid Leukemia
Venous Thrombosis
Vascular Endothelial Growth Factor A
Disease-Free Survival
Research Design
Stem Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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High-dose celecoxib and metronomic "low-dose" cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin's lymphoma. / Buckstein, Rena; Kerbel, Robert S.; Snaked, Yuval; Nayar, Rakesh; Foden, Cindy; Turner, Ruth; Lee, Christine R.; Taylor, Diane; Zhang, Liying; Man, Shan; Baruchel, Sylvain; Stempak, Diana; Bertolini, Francesco; Crump, Michael.

In: Clinical Cancer Research, Vol. 12, No. 17, 01.09.2006, p. 5190-5198.

Research output: Contribution to journalArticle

Buckstein, R, Kerbel, RS, Snaked, Y, Nayar, R, Foden, C, Turner, R, Lee, CR, Taylor, D, Zhang, L, Man, S, Baruchel, S, Stempak, D, Bertolini, F & Crump, M 2006, 'High-dose celecoxib and metronomic "low-dose" cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin's lymphoma', Clinical Cancer Research, vol. 12, no. 17, pp. 5190-5198. https://doi.org/10.1158/1078-0432.CCR-06-0474
Buckstein, Rena ; Kerbel, Robert S. ; Snaked, Yuval ; Nayar, Rakesh ; Foden, Cindy ; Turner, Ruth ; Lee, Christine R. ; Taylor, Diane ; Zhang, Liying ; Man, Shan ; Baruchel, Sylvain ; Stempak, Diana ; Bertolini, Francesco ; Crump, Michael. / High-dose celecoxib and metronomic "low-dose" cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin's lymphoma. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 17. pp. 5190-5198.
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abstract = "Purpose: Angiogenesis is increased in aggressive histology non-Hodgkin's lymphoma and may be a target with selective cyclooxygenase-2 inhibition and metronomic chemotherapy. Experimental Design: We assessed response, toxicity, and biomarkers of angiogenesis to low-dose cyclophosphamide (50 mg p.o. o.d.) and high-dose celecoxib (400 mg p.o. b.i.d.) in adult patients with relapsed or refractory aggressive non-Hodgkin's lymphoma in a multicenter phase II prospective study. Results: Thirty-two of 35 patients (median age, 62 years) are evaluable for response. Patients had primarily relapsed diffuse large B-cell lymphoma (63{\%}) were heavily pretreated (median of three regimens) and high risk (79{\%} international prognostic index, ≥2) and 34{\%} were relapsed after autologous stem cell transplant. With a median follow-up of 8.4 months, the overall best response rate is 37{\%} (2 complete clinical response/complete clinical response unconfirmed and 9 partial response), with 22{\%} achieving stable disease. Median overall and progression-free survivals are 14.4 and 4.7 months, respectively. The median response duration was 8.2 months. The most common toxicity was skin rash (40{\%}); myelosuppression and gastrointestinal side effects were uncommon. Three patients developed deep vein thromboses and two heavily pretreated patients developed treatment-related acute myelogenous leukemia or myelodysplasia after 3.7 and 12 months of therapy. Circulating endothelial cells and their precursors declined and remained low in responders, whereas plasma vascular endothelial growth factor trended to decline in responding patients but increase in nonresponders. Trough celecoxib levels achieved targeted {"}antiangiogenic{"} levels. Conclusions: Low-dose cyclophosphamide and high-dose celecoxib is well tolerated and active in pretreated aggressive non-Hodgkin's lymphoma. Close surveillance for arterial and venous thrombotic events is recommended. The decline in circulating endothelial cells and their precursors suggests that this combination may be working by inhibiting angiogenesis but should be validated in a larger patient sample.",
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T1 - High-dose celecoxib and metronomic "low-dose" cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin's lymphoma

AU - Buckstein, Rena

AU - Kerbel, Robert S.

AU - Snaked, Yuval

AU - Nayar, Rakesh

AU - Foden, Cindy

AU - Turner, Ruth

AU - Lee, Christine R.

AU - Taylor, Diane

AU - Zhang, Liying

AU - Man, Shan

AU - Baruchel, Sylvain

AU - Stempak, Diana

AU - Bertolini, Francesco

AU - Crump, Michael

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N2 - Purpose: Angiogenesis is increased in aggressive histology non-Hodgkin's lymphoma and may be a target with selective cyclooxygenase-2 inhibition and metronomic chemotherapy. Experimental Design: We assessed response, toxicity, and biomarkers of angiogenesis to low-dose cyclophosphamide (50 mg p.o. o.d.) and high-dose celecoxib (400 mg p.o. b.i.d.) in adult patients with relapsed or refractory aggressive non-Hodgkin's lymphoma in a multicenter phase II prospective study. Results: Thirty-two of 35 patients (median age, 62 years) are evaluable for response. Patients had primarily relapsed diffuse large B-cell lymphoma (63%) were heavily pretreated (median of three regimens) and high risk (79% international prognostic index, ≥2) and 34% were relapsed after autologous stem cell transplant. With a median follow-up of 8.4 months, the overall best response rate is 37% (2 complete clinical response/complete clinical response unconfirmed and 9 partial response), with 22% achieving stable disease. Median overall and progression-free survivals are 14.4 and 4.7 months, respectively. The median response duration was 8.2 months. The most common toxicity was skin rash (40%); myelosuppression and gastrointestinal side effects were uncommon. Three patients developed deep vein thromboses and two heavily pretreated patients developed treatment-related acute myelogenous leukemia or myelodysplasia after 3.7 and 12 months of therapy. Circulating endothelial cells and their precursors declined and remained low in responders, whereas plasma vascular endothelial growth factor trended to decline in responding patients but increase in nonresponders. Trough celecoxib levels achieved targeted "antiangiogenic" levels. Conclusions: Low-dose cyclophosphamide and high-dose celecoxib is well tolerated and active in pretreated aggressive non-Hodgkin's lymphoma. Close surveillance for arterial and venous thrombotic events is recommended. The decline in circulating endothelial cells and their precursors suggests that this combination may be working by inhibiting angiogenesis but should be validated in a larger patient sample.

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