A phase II study of high-dose celecoxib and metronomic ‘low-dose‘ cyclophosphamide and methotrexate in patients with relapsed and refractory lymphoma

Bary, Naser Abd El; Hashem, Tarek; Metwally, Hasan; Ghany, Ashraf Abd; Mageed, Hager Abd El

doi:10.1016/s1658-3876(10)50051-7

Cited by 15 publications

(9 citation statements)

References 12 publications

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“…In Buckstein study, three patients developed venous thrombosis this was explained as a recognized complication in the treatment of NHL, especially at advanced stage. There was no such side effect observed in our study nor Abd El Bary study 9,11 . The main limitation of the study is the lack of control arm, small sample size and short follow up time.…”

Section: Rituximab In Diffuse Large B Cell Lymphomacontrasting

confidence: 57%

“…There is only two published studies regarding the use of metronomic chemotherapy in treatment of relapsed and/or refractory NHL, one by Buckstein et al 9 , while the other one by Abd El Bary et al 11 in which patients were enrolled to receive oral combination of highdose celecoxib and low-dose Cyclophosphamide, The preclinical data provide the rationale for using low dose chemotherapy together with selective COX-2 inhibitors in the treatment of DLBCL. The combination of low dose cyclophosphamide and methotrexate was chosen in this combination based on preclinical and clinical data.…”

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confidence: 99%

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One Year of Maintenance Metronomic Cyclophosphamide, Methotreaxate & Celecoxib in High Risk Diffuse Large B Cell Non Hodgkin Lymphoma After Complete Response.

Alhassanin

Hashem

Eldin

et al. 2014

Kasr-Al-Aini J.of Clin. Onc. and Nuc. Med.

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IntroductIonCombination chemotherapy with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) has been the mainstay of treatment for several decades with complete response rates (RR) of 45-55% and cure rates of approximately 30-35% in aggressive NHL; the addition of the immunotherapeutic agent Rituximab to chemotherapy (R-CHOP) has improved complete RR to 76-86% and OS rates significantly. Nevertheless, variability in response rates, and particularly in event free survival (EFS) and OS, have been observed in these trials, and up to one-third of all patients experience progression or relapse of their disease. Outcomes in relapsed or refractory DLBCL are poor, with a median survival approximating 6 months. Salvage chemotherapy followed by high-dose therapy and autologous stemcell transplantation (HDT-ASCT) is widely considered the standard treatment for relapsed DLBCL, though the ORR and EFS are significantly lower in this setting as compared to those observed in upfront treatment. Many patients, moreover, are not eligible for transplant, and of those that are, about half fail to respond to salvage therapy, becoming ineligible for HDT-ASCT 1 .Recent data indicate that angiogenesis is important in the pathophysiology and prognosis of aggressive histologic subtypes of NHL 2 . Angiogenesis and angiogenic factors are increased in most lymphomas. In addition, angiogenesis has been associated with adverse outcomes or more aggressive clinical behavior in malignant lymphoma. However, the role of angiogenesis might vary in lymphoma subtypes because of the prognostic value of microvessel density and the different Surgical department-Faculty of medicine-Menofia University-Egypt.Background & purpose: Diffuse large B cell lymphoma (DLBCL) is the most common subtype of NonHodgkin lymphoma (NHL). Although cure rates are increased after the addition of Rituximab to the standard CHOP; yet there is a significant number -especially of high risk-patients get relapse and have a poor response to second-line regimens. Novel approaches are needed for DLBCL treatment. We conducted this trial to evaluate the role of metronomic maintenance chemotherapy in patients with high risk DLBCL who enter in complete response (CR) after first line standard chemotherapy. Patients and methods: this is a prospective phase II single arm study done on 40 patients with high risk DLBCL. All patients received metronomic maintenance chemotherapy for one year (who had CR after standard R-CHOP) in the form of oral Cyclophosphamide (50 mg every day), oral Methotrexate (2.5 mg 4 times/week) and high-dose oral Celecoxib (400 mg twice daily). results: thirty five and 65 percent of patients presented with stage III and IV respectively, 29 patients (72.5%) had international prognostic index (IPI) score of 3 (high intermediate), while11 patients (27.5%) had IPI score of 4 or 5 (high). The most common toxicity was grade I and II hematological and gastrointestinal toxicity. Grade I fatigue was the most remarkable side effect noticed in 27.5% of patients. N...

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Section: Rituximab In Diffuse Large B Cell Lymphomacontrasting

confidence: 57%

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confidence: 99%

One Year of Maintenance Metronomic Cyclophosphamide, Methotreaxate & Celecoxib in High Risk Diffuse Large B Cell Non Hodgkin Lymphoma After Complete Response.

Alhassanin

Hashem

Eldin

et al. 2014

Kasr-Al-Aini J.of Clin. Onc. and Nuc. Med.

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“…Modulation of numerous apoptotic proteins after treatment by celecoxib can slightly induce B-lymphoma cell death. Then, celecoxib can play the role of a sensitizer to cell death and acts synergistically with different chemotherapeutic drugs (48,49) or the new therapeutic proapoptotic molecule TRAIL in the induction of tumor cell cytotoxicity. It could be interesting to further evaluate whether the ability of celecoxib to downregulate Mcl-1 expression could bypass the mechanism of resistance to rituximab, associated with an upregulation of Mcl-1 (50).…”

Section: Discussionmentioning

confidence: 99%

COX-2–Independent Effects of Celecoxib Sensitize Lymphoma B Cells to TRAIL-Mediated Apoptosis

Gallouët

Travert

Bresson

et al. 2014

Clinical Cancer Research

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Purpose: Despite therapeutic advances, non-Hodgkin lymphomas (NHL) remain incurable. They form a group of neoplasms strongly dependent on their inflammatory microenvironment, which plays an important supportive role in tumor B-cell survival and in the resistance to antitumor immune response. New therapies must consider both tumor cells and their surrounding microenvironment Experimental Design: Stromal cells, derived from bone marrow or lymph nodes, and B cells from follicular lymphoma patients were cocultured or cultured alone with celecoxib treatment, a nonsteroidal anti-inflammatory drug, and/or TRAIL, a promising cytotoxic molecule for cancer therapy.Results: In this study, we show that follicular lymphoma stromal cells produce large amounts of PGE 2 . This production is abrogated after celecoxib treatment, targeting the COX-2 isoenzyme involved in PGE 2 synthesis. Furthermore, we demonstrate that celecoxib increases apoptosis in NHL B-cell lines and in primary follicular lymphoma B cells cocultured with stromal cells, but independently of the PGE 2 /COX-2 axis. Finally, celecoxib increases the apoptotic activity of TRAIL. We provide evidence that celecoxib affects proliferation and sensitizes NHL B-cell lines to apoptosis through COX-2-independent effects by slowing down the cell cycle and decreasing the expression of survival proteins, such as Mcl-1.Conclusions: These data suggest new potent strategies for NHL therapy combining drugs targeting both tumor B cells and survival signals provided by the tumor microenvironment.

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“…E7123 induced tumor growth retardation in a mouse model of DLBCL after its oral administration, and it was tolerated without toxicity. Interestingly, the E7123 parent compound, celecoxib, in combination with cyclophosphamide, has shown activity in phase 2 studies with primary relapsed DLBCL, 47,48 although close surveillance for arterial and venous thrombotic events has been recommended. These cardiovascular side effects are associated with COX-2 inhibition.…”

Section: Discussionmentioning

confidence: 99%

A novel inhibitor of focal adhesion signaling induces caspase-independent cell death in diffuse large B-cell lymphoma

Bosch

Dieguez-Gonzalez²,

Céspedes

et al. 2011

Blood

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Focal adhesion (FA) proteins have been associated with transformation, migration, metastasis, and poor outcome in many neoplasias. We previously showed that these proteins were inhibited by E7123, a new celecoxib derivative with antitumor activity, in acute myeloid leukemia. However, little is known about FAs in diffuse large B cell lymphoma (DLBCL). This paper aimed to determine whether E7123 was effective against DLBCL and whether FAs were involved in its action.We evaluated the cytotoxicity and mechanism of action of E7123 and celecoxib in DLBCL cell lines. We also assessed the E7123 in vivo activity in a DLBCL xenograft model and studied FA signaling in primary DLBCL patient samples. We found that E7123 showed higher antitumor effect than celecoxib against DLBCL cells. Its mechanism of action involved deregulation of FA, AKT, and Mcl-1 proteins, a pathway that is activated in some patient samples, apoptosis-inducing factor release and induction of caspase-independent cell death. Moreover, E7123 showed suppression of in vivo tumor growth. These findings indicate that E7123 is effective against DLBCL in vitro and in vivo, with a mechanism of action that differs from that of most current therapies for this malignancy. IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin lymphoma subtype. Cure rates have increased in recent years with the addition of rituximab to the combination chemotherapy: cyclophosphamide, doxorubicin, vincristine, and prednisone. 1 However, a significant percentage of patients still relapse because lymphoma cells acquire resistance to therapy, which is associated with defective caspase-dependent apoptotic pathways. [2][3][4] Paradoxically, almost all cytotoxic drugs currently in clinical use for DLBCL induce caspase-dependent apoptosis. 5 Thus, the development of novel compounds with mechanisms of action able to induce caspase-independent cell death probably improves the therapeutic outcome in DLBCL, particularly in patients who relapse after front-line therapy.Focal adhesion (FA) complexes are structures that link the actin filaments of the cytoskeleton with the extracellular matrix. They are formed by transmembrane receptors (integrins) that activate various protein kinases, including the focal adhesion kinase (FAK) and Src family kinases. 6 Crk-associated substrate (CAS) family proteins act as docking proteins that associate with FAK and Src to generate specific cellular responses. 7 FA proteins have been related to transformation, 8 migration, 9 metastasis, 10 and poor outcome 11 in many solid tumors and in some hematologic malignancies. 12,13 However, there are limited data regarding the role of FA proteins in DLBCL. To our knowledge, only FAK and the Src-family protein LYN have been studied in DLBCL. FAK is expressed in 70% of DLBCLs 14 and LYN is constitutively phosphorylated and required for DLBCL growth, survival, and proliferation. 15,16 Other FA proteins, such as HEF1 or p130Cas from the CAS family, or PYK2 from the FAK family, play crucial roles ...

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A phase II study of high-dose celecoxib and metronomic ‘low-dose‘ cyclophosphamide and methotrexate in patients with relapsed and refractory lymphoma

Cited by 15 publications

References 12 publications

One Year of Maintenance Metronomic Cyclophosphamide, Methotreaxate & Celecoxib in High Risk Diffuse Large B Cell Non Hodgkin Lymphoma After Complete Response.

One Year of Maintenance Metronomic Cyclophosphamide, Methotreaxate & Celecoxib in High Risk Diffuse Large B Cell Non Hodgkin Lymphoma After Complete Response.

COX-2–Independent Effects of Celecoxib Sensitize Lymphoma B Cells to TRAIL-Mediated Apoptosis

A novel inhibitor of focal adhesion signaling induces caspase-independent cell death in diffuse large B-cell lymphoma

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