Bevacizumab as a treatment for hereditary hemorrhagic telangiectasia in children: a case report / Bevacizumab como tratamiento para telangiectasia hemorrágica hereditaria en niños: Reporte de caso

Abstract Case description: Five-year-old female patient with hereditary hemorrhagic telangiectasia. Clinical Findings: Deterioration of cardiopulmonary function with higher oxygen requirements secondary to pulmonary arteriovenous shunts, epistaxis. Treatment and Outcome: The patient was treated with the monoclonal antibody bevacizumab, which inhibits the vascular endothelial growth factor, with good clinical outcome. Clinical Relevance: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations in different organs, making its clinical presentations varied. Systemic therapeutic options for a generalized disease are limited. The monoclonal antibody bevacizumab, seems to be a good option in this disorder. Although reported as successful in adult population, its use in pediatric population has not yet been reported. Here we report the use of bevacizumab in a 5-year-old female patient with hereditary hemorrhagic telangiectasia, showing clinical benefits and good outcome.

Resumen Descripción del caso: Paciente de cinco años de sexo femenino con telangiectasia hemorrágica hereditaria. Hallazgos Clínicos: Deterioro de la función cardiopulmonar con mayores requerimientos de oxígeno secundario a shunt pulmonar arteriovenoso, epistaxis. Tratamiento y resultado: La paciente fue tratada con el anticuerpo monoclonal bevacizumab, que inhibe el factor de crecimiento endotelial vascular, con buen resultado clínico. Relevancia clínica: La telangiectasia hemorrágica hereditaria es un trastorno autosómico dominante caracterizado por malformaciones arteriovenosas en diferentes órganos, lo que hace que sus presentaciones clínicas varíen. Las opciones terapéuticas sistémicas para la enfermedad generalizada son limitadas. El anticuerpo monoclonal bevacizumab, parece ser una buena opción en este trastorno. Aunque se ha reportado como exitoso en la población adulta, su uso en población pediátrica aún no ha sido reportado. Aquí se informa el uso de bevacizumab en una paciente de 5 años de edad con telangiectasia hemorrágica hereditaria, mostrando beneficios clínicos y buen resultado.

Safety and feasibility of the use of a bevacizumab-methylcellulose mixture as an adjunct to glaucoma surgery: a pilot study / Segurança e viabilidade do uso de uma mistura de bevacizumabe-metilcelulose como terapia adjuvante à cirurgia anti-glaucomatosa: um estudo piloto

ABSTRACT Bevacizumab, a monoclonal anti-vascular endothelial growth factor antibody, has been suggested as a potential healing therapeutic following glaucoma surgery. Here, we aimed to improve the bioavailability of bevacizumab when used as an adjunct therapy to non-penetrating deep sclerectomy (DS) by using a bevacizumab-methylcellulose mixture (BMM). Ten previously non-operated eyes in ten patients diagnosed with primary open angle glaucoma underwent DS with a subconjunctival injection of 0.3 ml of BMM (bevacizumab 3.75 mg incorporated into 4% methylcellulose) at the surgical site. Bevacizumab release was evaluated in vitro using size-exclusion high performance liquid chromatography (HPLC). Intraocular pressure (IOP), bleb morphology, corneal endothelial cell count (CECC), and complications were evaluated at 6 months after surgery. Using HPLC, bevacizumab was detected in BMM for up to 72 h. Moreover, all surgical blebs remained expanded with hyaline material during the first week. A significant IOP reduction (mean ± SD= -10.3 ± 5.4 mmHg, P<0.001) and diffuse blebs were observed at the final follow-up period. Although CECC was slightly reduced (-7.4%), no complications were observed. In conclusion, bevacizumab was released from BMM, and the use of this innovative mixture yielded good results following DS with no complications. Further studies are required to determine its efficacy prior to establishing BMM as an adjunct treatment for penetrating and non-penetrating glaucoma surgeries.

RESUMO O bevacizumabe (um agente anti-fator de crescimento endotelial vascular) tem sido sugerido como potencial modulador cicatricial na cirurgia do glaucoma. Este estudo objetivou melhorar a biodisponibilidade do bevacizumabe, investigando a viabilidade de uma nova mistura de bevacizumabe-metilcelulose (BMM) como terapia adjuvante para a esclerectomia profunda não-penetrante (DS). Dez olhos sem cirurgias prévias de 10 pacientes com glaucoma primário de ângulo aberto foram submetidos à DS associada à uma injeção subconjuntival de 0,3 ml da mistura de bevacizumabe-metilcelulose (bevacizumabe 3,75 mg incorporado em metilcelulose 4%) no sítio cirúrgico. A liberação de bevacizumabe foi avaliada in vitro através de cromatografia líquida de alta performance por exclusão de tamanho (HPLC). A pressão intraocular (PIO), a morfologia da ampola de filtração, a contagem de células endoteliais da córnea (CECC) e as complicações foram estudadas aos seis meses de seguimento. O bevacizumabe foi detectado a partir da mistura de bevacizumabe-metilcelulose por meio do HPLC até 72 horas. Além disso, todas as ampolas cirúrgicas permaneceram expandidas com material hialino durante a primeira semana. Uma redução significativa da pressão intraocular (média ± DP= -10,3 ± 5,4 mmHg, P<0,001) e ampolas difusas foram observadas ao final do período de seguimento. Embora a contagem de células endoteliais da córnea se mostrou discretamente diminuída (-7,4%), nenhuma complicação foi observada. Neste estudo, o bevacizumabe foi liberado da mistura de bevacizumabe-metilcelulose e o uso desta nova mistura se associou com bons resultados cirúrgicos e nenhuma complicação. Estudos futuros serão necessários para determinar sua eficácia, antes de se estabelecer a mistura de bevacizumabe-metilcelulose como um tratamento adjuvante às cirurgias penetrantes e não-penetrantes para o glaucoma.

Effects of Bevacizumab on Bcl-2 Expression and Apoptosis in Retinal Pigment Epithelial Cells under Oxidative Stress

PURPOSE: To evaluate the effects of bevacizumab on expression of B-cell leukemia/lymphoma (Bcl)-2 and apoptosis in retinal pigment epithelial (RPE) cells under oxidative stress conditions. METHODS: RPE cells were treated with H2O2 (0, 100, 200, 300, and 400 microM) and bevacizumab at or above the doses normally used in clinical practice (0, 0.33, 0.67, 1.33, and 2.67 mg/mL). Cell apoptosis was measured using flow cytometry with annexin V-fluorescein isothiocyanate. The expression of Bcl-2 mRNA was determined using reverse transcription polymerase chain reaction. RESULTS: Under low oxidative stress conditions (H2O2 100 microM), cell apoptosis was not significantly different at any concentration of bevacizumab, but Bcl-2 mRNA expression decreased with increasing concentration of bevacizumab (0.33, 0.67, 1.33, and 2.67 mg/mL). Under moderate oxidative stress conditions (H2O2 200 microM), Bcl-2 mRNA expression decreased with increasing concentration of bevacizumab (0.33, 0.67, 1.33, and 2.67 mg/mL), but cell apoptosis increased only at 2.67 mg/mL of bevacizumab. Under high oxidative stress (300 microM) conditions, cell apoptosis increased at high concentrations of bevacizumab (1.33 and 2.67 mg/mL), but it did not correlate with Bcl-2 expression. CONCLUSIONS: Withdrawal of vascular endothelial growth factor can lead to RPE cell apoptosis and influences the expression of anti-apoptotic genes such as Bcl-2 under oxidative stress conditions. Since oxidative stress levels of each patient are unknown, repeated injections of intravitreal bevacizumab, as in eyes with age-related macular degeneration, might influence RPE cell survival.

Critical evaluation of the off-label indication and of the risks associated to the use of multi-dose vials on the treatment of age-related macular degeneration

Age-related macular degeneration (AMD) is an ocular inflammatory diseases treated mainly by means of a bevacizumab (Avastin®) or ranibizumab (Lucentis®) intravitreal injection. Among these drugs, only ranibizumab has a specific therapeutic indication for AMD. Considering that, the off-label use on ophthalmic therapy seems to become a rule when it should be an exception. Furthermore, bevacizumab presentation consists of multi-dose vials although it does not contain preservatives in its formula. The current literature review aimed at assessing the risks for the patient related to the use of off-label indication and multi-dose vials on AMD treatment. Considering this, the proposal related to the Brazilian Public Consultation no.10, dated September 12, 2012, which proposes the Clinical Protocol and Therapeutic Guidelines for AMD treatment, was evaluated. This systematic review allowed to conclude that the bevacizumab off-label indication results in increased risks for the patient when compared to the product with specific therapeutic indication for AMD treatment (ranibizumab), especially referring to the significant raise in the adverse events. The risks for the patient related to the multi-dose vial use, referring to the microbiological stability and dose precision, were also made clear.

A degeneração macular relacionada à idade (DMRI) é uma doença ocular inflamatória tratada principalmente por injeção intravítrea de bevacizumabe (Avastin®) ou de ranibizumabe (Lucentis®). Entre os medicamentos citados, apenas o ranibizumabe tem indicação terapêutica específica para uso oftálmico. Considerando essa realidade, o uso off-label na terapia oftálmica parece constituir regra quando deveria ser exceção. Ademais, a apresentação do bevacizumabe consiste em frascos de múltipla-dose, embora esse medicamento não contenha conservante em sua fórmula. A presente revisão da literatura avaliou os riscos ao paciente relativos ao uso indicado off-label e de frascos de múltipla-dose no tratamento de DMRI. Nesse sentido, avaliou-se a proposta relativa à Consulta Pública Brasileira nº 10, de 12 de setembro de 2012, que propõe o Protocolo Clínico e Diretrizes Terapêuticas para o tratamento de DMRI. O levantamento sistemático de trabalhos científicos e de informações relevantes de banco de dados eletrônicos permitiu concluir que a indicação off-label do bevacizumabe acarreta riscos maiores ao paciente, quando comparado ao produto com indicação terapêutica específica para o tratamento de DMRI (ranibizumabe), especialmente quanto ao aumento significativo de eventos adversos. Evidenciaram-se, também, os riscos ao paciente relativos ao uso de frascos de múltipla-dose, quanto à estabilidade microbiológica e à precisão da dose.