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

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 lowdose 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, z2) 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 are14.4 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.

Safety and Therapeutic Effect of Metronomic Chemotherapy with Cyclophosphamide and Celecoxib in Advanced Breast Cancer Patients

“…Accordingly, a study in ovarian cancer patients showed that high circulating CEPs correlated with poor overall survival [52]. On the contrary, other studies in Hodgkin lymphoma [20] and breast cancer [19] patients, showed a decrease of CEPs and/or CECs, when treated with Cy plus Cel or Cy plus capecitabine and bevacizumab, respectively Our preliminary results, together with data from other reports, are yet scarce to consider the use of CEPs or CECs as biomarkers to identify patients who are candidates to antiangiogenic therapy, but may be useful to evaluate treatment response after its initiation.…”

“…The promising results obtained, in terms of therapeutic efficacy, good tolerability and low toxicity profile together with previous clinical experience by others setting the metronomic dose of Cy [19,20] prompted us to conduct a phase I/II trial employing metronomic administration of Cy combined with Cel for the treatment of metastatic breast cancer (MBC) patients progressing after standard chemotherapy.…”

Targeting Cyclooxygenase-2 in Hematological Malignancies: Rationale and Promise

“…As previously mentioned, Cox-2 expression in Hodgkin's lymphoma correlated with a greater degree of angiogenesis [3]. In a phase II clinical trial, Buckstein, et al, gave relapsed or refractory diffuse large B cell lymphoma patients celecoxib with cyclophosphamide chemotherapy in an attempt to reduce angiogenic factors [79]. Indicators of angiogenesis were decreased in responding patients, including a reduction in serum VEGF levels and fewer circulating endothelial cells and endothelial cell precursors.…”

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

“…54 Combination of LDM CTX with celecoxib in heavily pretreated patients contributed to an impressive duration of stable disease with no toxicity, 45 whereas this combination is also effective in treating refractory high-grade lymphoma. 55 The combination of CTX plus weekly vinblastine and rofecoxib is effective for a subset of Hodgkin's disease patients. 56 CTX has also been used with low-dose methotrexate in the treatment of early breast cancer and the inhibition of angiogenesis is caused by a decrease in vascular endothelial growth factor.…”