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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

Authors' Affiliations: ¹ Medical Oncology, Toronto Sunnybrook Regional Cancer Centre; ² Molecular and Cell Biology, Sunnybrook and Women's College Health Sciences Center; ³ Medical Oncology, Princess Margaret Hospital; ⁴ Medical Oncology, Hospital for Sick Children, Toronto, Ontario, Canada and ⁵ European Institute of Oncology, Milan, Italy

Requests for reprints: Rena Buckstein, Toronto Sunnybrook Regional Cancer Center, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3 M5. Phone: 416-480-5847; Fax: 416-480-6002; E-mail: rena.buckstein{at}sw.ca.

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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