RESUMO
STOP-CA was a multicenter, double-blind, randomized, placebo-controlled trial comparing atorvastatin to placebo in treatment-naïve lymphoma patients receiving anthracycline-based chemotherapy. We performed a preplanned subgroup to analyze the impact of atorvastatin on efficacy in patients with diffuse large B-cell lymphoma (DLBCL). Patients received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at standard doses for six 21-day cycles and were randomly assigned to receive atorvastatin 40 mg daily (n = 55) or placebo (n = 47) for 12 months. The complete response (CR) rate was numerically higher in the atorvastatin arm (95% [52/55] vs. 85% [40/47], p = .18), but this was not statistically significant. Adverse event rates were similar between the atorvastatin and placebo arms. In summary, atorvastatin did not result in a statistically significant improvement in the CR rate or progression-free survival, but both were numerically improved in the atorvastatin arm. These data warrant further investigation into the potential therapeutic role of atorvastatin added to anthracycline-based chemotherapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Atorvastatina , Ciclofosfamida , Doxorrubicina , Linfoma Difuso de Grandes Células B , Prednisona , Rituximab , Vincristina , Humanos , Atorvastatina/uso terapêutico , Atorvastatina/administração & dosagem , Atorvastatina/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Prednisona/uso terapêutico , Prednisona/efeitos adversos , Prednisona/administração & dosagem , Vincristina/uso terapêutico , Vincristina/efeitos adversos , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Rituximab/administração & dosagem , Doxorrubicina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/administração & dosagem , Ciclofosfamida/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Método Duplo-Cego , Resultado do Tratamento , AdultoRESUMO
PURPOSE: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms. EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation. RESULTS: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy. CONCLUSIONS: Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.