Infliximab Efficacy in Relation to Therapeutic Drug Monitoring and Serum Tumor Necrosis Factor (TNF)α Levels in Pediatric HSCT Recipients With Acute Graft-versus-host Disease: a Prospective Observational Study
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Correlation between TNFalpha and infliximab plasma concentrations at day +56 of treatment
研究概览
简要总结
In children receiving a hematopoietic stem cell transplant (HSCT), blood levels of TNFalpha (an inflammatory cytokine) at the onset of the acute GVHD (graft-versus-host disease) could be correlated with the severity of the disease. The hypothesis is that the highest infliximab (a biologic drug against TNFalpha) could be associated with a significant reduction in TNFa levels and, subsequently, with a faster remission of the symptoms and prevention of disease progression. Moreover, a rapid drop of infliximab serum concentration, documented by therapeutic drug monitoring (TDM), could be related to the active phase of GVHD and higher production of TNFalpha. Therefore, the study is aimed at investigating whether the drop in infliximab plasma concentrations could be associated with clinical response and production of TNFalpha.
HSCT children receiving infliximab to control GVHD are enrolled. Blood samples will be collected during treatment and they serve to measure drug and TNFalpha concentrations. Drug levels are analyzed by a population pharmacokinetic modeling and results are compared with plasma concentrations of TNFalfa and clinical response.
详细描述
Despite significant progress in overall survival and event-free survival in Pediatric Hematopoietic Stem Cell Transplant (HSCT), therapeutic options for graft-versus-host disease (GVHD) control remain limited, particularly in steroid-refractory patients. Several strategies have been proposed in the last 20 years but so far the results have been mixed and inconclusive, complicated by the small population afflicted, inconsistent treatment schedules, diverse disease classifications, and diagnosis methods. The number of studies concerning pediatric patients is even smaller.
First-line therapy for acute GVHD is steroid treatment that achieves partial or complete remission of the disease in a variable percentage (40-60%) of cases, depending mainly on the severity of GVHD and number of organ involvement. Notably, hepatic and gastrointestinal GVHD is particularly refractory to steroid treatment.
For second-line therapy, there is no standardized strategy with a great variety of immunosuppressive treatments without a real superiority of a drug in comparison to another.
Steroid refractory acute GVHD is therefore one of the most important challenges in the HSCT field. One of the more promising routes, based on published data and clinical experience, is the off-label use of Infliximab, an anti-Tumor Necrosis Factor (TNF)alpha drug (already approved for many rheumatological and autoimmune diseases) administered as a second-line treatment in patients with steroid-refractory acute GVHD at the standardized dosage of 10 mg/kg, although, to our knowledge, no substantial evidence has been published to validate this subscription. The biological pattern that could explain the susceptibly of GVHD to infliximab treatment could lie in the physiopathology of acute gastrointestinal GVHD that may resemble ulcerative rectocolitis. In this case, relation to Therapeutic Drug Monitoring (TDM) and TNFalpha levels could be critical in monitoring the efficacy of the drug and the need for further doses.
Published data, scarce as it may be, and clinical experience showed that infliximab may be able to further control symptoms and inflammatory response in a promising percentage of treated patients, although some have no benefit from the treatment.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Allogeneic HSCT recipient;
- •Onset of clinical signs of acute skin, gastrointestinal or hepatic GVHD according to the Glucksberg classification;
- •At least five days of steroid treatment (minimum 1 mg/kg of methylprednisone or equivalent) for systemic aGVHD without clinical or laboratory signs of response or no steroid treatment for onset of grade I-II hepatic/gastroesophageal/intestinal isolated aGVHD;
- •Patients who consent for the off-label use of infliximab and data processing for research purposes based on the institutional model GECO;
- •At least one dose of infliximab received during aGVHD management;
- •Minimum follow-up after infliximab administration: 6 months
排除标准
- •Follow up < 6 months.
- •Active fungal or bacterial infection with life-threatening clinical condition (shock or respiratory distress that needs mechanical ventilation)
结局指标
主要结局
Correlation between TNFalpha and infliximab plasma concentrations at day +56 of treatment
时间窗: Day 56 after the start of infliximab administration
Correlation analysis between TNFalpha and infliximab plasma concentrations at day +56 of treatment
次要结局
- Retreatment rate with infliximab after the first dose(From +90 days from treatment begin up to +1 year)
- Correlation between TNFalpha and infliximab plasma concentrations at day +7 of treatment(Day +7 after the start of infliximab administration)
- Overall survival (OS)(From day +100, up to +1 year after HSCT)
- Relationship between baseline TNFalpha plasma concentration and aGVHD overall severity(From day -7 up to day -1 from the start of infliximab administration)
- Percentage of transplant-related deaths and infections during follow-up(From +6 months up to +1 year after treatment)
- Clinical response to infliximab(Day +56 of treatment)
- Infliximab plasma concentrations according to clinical response(From day +7 up to day +56 of treatment)
- Safety of drug treatment(From day +100 up to +1 year post-HSCT)
研究者
Antonello Di Paolo, M.D., Ph.D.
Associate Professor of Pharmacology
University of Pisa