Infliximab Efficacy in Relation to Therapeutic Drug Monitoring and Serum TNFα Levels in Pediatric HSCT

Study Overview
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Brief Summary
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Despite significant progress in overall survival and event-free survival in Pediatric Hematopoietic Stem Cell Transplant (HSCT), therapeutic options for graft-versus-host disease 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 inconclusive, complicated by the small population afflicted, inconsistent treatment schedules, different disease classifications and diagnosis methods. The number of studies concerning pediatric patients are even smaller. First line therapy for acute graft-versus-host disease (aGVHD) is steroid treatment that achieve partial or complete remission of the disease in a variable percentage of cases (40-60%), depending mainly to severity of GVHD and number of organ involvement, with hepatic and gastrointestinal GVHD particularly refractory to steroid treatment. For second line therapy there is no a standardized strategy with a great variety of immunosuppressive treatment without a real superiority of a drug in comparison to another. Steroid refractory acute GVHD is therefore one of the most important challenges in 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 α drug (already approved for many rheumatologic and autoimmune diseases) administered as a second line treatment in patients with steroid-refractory aGVHD at the standardized dosage of 10 mg/kg, although limited evidence has been published to validate this subscription. Biological pattern that could explain susceptibly of GVHD to infliximab treatment could lie in physiopathology of acute gastrointestinal GVHD that may resemble ulcerative rectocolitis. In this case, relation to Therapeutic Drug Monitoring (TDM) and Tumor Necrosis Factor α (TNFα) levels could be critical in monitoring the efficacy of the drug and need of further doses. Limited published data and clinical experience show 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. The aim of this study is to analyze the role of TNFα concentration in aGVHD, its levels fluctuation and clinical response of GVHD to Infliximab treatment in steroid-refractory pediatric patients.

Official Title
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Infliximab Efficacy in Relation to Therapeutic Drug Monitoring and Serum Tumor Necrosis Factor (TNF)α Levels in Pediatric Hematopoietic Stem Cell Transplant Recipients

Conditions
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Acute Graft-versus-host Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of the patients between 0 and 18; 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; At least one dose of infliximab received during aGVHD management; Minimum follow-up after infliximab administration of 6 months Exclusion Criteria: Active fungal or bacterial infection with life-threatening clinical condition (shock or respiratory distress needing mechanical ventilation)

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between TNFα plasmatic concentration and serum infliximab levels | TNFα levels and infliximab concentration will be measured in peripheral blood sample (serum) | At day 56 after starting infliximab treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between TNFα concentration and serum infliximab levels | TNFα levels and infliximab concentration will be measured in peripheral blood sample (serum) | At day 7 after starting infliximab treatment | 
| Association between Baseline TNFα concentration and aGVHD overall severity | TNFα levels will be measured in peripheral blood sample (serum) | Before starting infliximab treatment | 
| Number of patients who achieved a significant drop of TNFα concentration after infliximab treatment | TNFα levels will be measured in peripheral blood sample (serum) | At day 7 after starting infliximab treatment | 
| Number of patients who achieved a significant drop of TNFα concentration after infliximab treatment | TNFα levels will be measured in peripheral blood sample (serum) | At day 14 after starting infliximab treatment | 
| Number of patients who achieved a significant drop of TNFα concentration after infliximab treatment | TNFα levels will be measured in peripheral blood sample (serum) | At day 28 after starting infliximab treatment | 
| Number of patients who achieved a significant drop of TNFα concentration after infliximab treatment | TNFα levels will be measured in peripheral blood sample (serum) | At day 42 after starting infliximab treatment | 
| Number of patients who achieved a significant drop of TNFα concentration after infliximab treatment | TNFα levels will be measured in peripheral blood sample (serum) | At day 56 after starting infliximab treatment | 
| Response to infliximab treatment for aGVHD | Number of patients who had Complete Response (CR), Partial Response (PR) or Non-Response (NR). Response is defined as complete resolution of GVHD symptoms and normalization of the biochemical parameters of inflammation. | At day 7 after starting infliximab treatment | 
| Response to infliximab treatment for aGVHD | Number of patients who had Complete Response (CR), Partial Response (PR) or Non-Response (NR). Response is defined as complete resolution of GVHD symptoms and normalization of the biochemical parameters of inflammation. | At day 14 after starting infliximab treatment | 
| Response to infliximab treatment for aGVHD | Number of patients who had Complete Response (CR), Partial Response (PR) or Non-Response (NR). Response is defined as complete resolution of GVHD symptoms and normalization of the biochemical parameters of inflammation. | At day 28 after starting infliximab treatment | 
| Response to infliximab treatment for aGVHD | Number of patients who had Complete Response (CR), Partial Response (PR) or Non-Response (NR). Response is defined as complete resolution of GVHD symptoms and normalization of the biochemical parameters of inflammation. | At day 42 after starting infliximab treatment | 
| Response to infliximab treatment for aGVHD | Number of patients who had Complete Response (CR), Partial Response (PR) or Non-Response (NR). Response is defined as complete resolution of GVHD symptoms and normalization of the biochemical parameters of inflammation. | At day 56 after starting infliximab treatment | 
| Infliximab serum concentration in patients with clinical CR, PR, NR. | Infliximab concentration will be measured in peripheral blood sample (serum). Response is defined as complete resolution of GVHD symptoms and normalization of the biochemical parameters of inflammation. | At day 7 after starting infliximab treatment | 
| Infliximab serum concentration in patients with clinical CR, PR, NR. | Infliximab concentration will be measured in peripheral blood sample (serum). Response is defined as complete resolution of GVHD symptoms and normalization of the biochemical parameters of inflammation. | At day 14 after starting infliximab treatment | 
| Infliximab serum concentration in patients with clinical CR, PR, NR. | Infliximab concentration will be measured in peripheral blood sample (serum). Response is defined as complete resolution of GVHD symptoms and normalization of the biochemical parameters of inflammation. | At day 28 after starting infliximab treatment | 
| Infliximab serum concentration in patients with clinical CR, PR, NR. | Infliximab concentration will be measured in peripheral blood sample (serum). Response is defined as complete resolution of GVHD symptoms and normalization of the biochemical parameters of inflammation. | At day 42 after starting infliximab treatment | 
| Infliximab serum concentration in patients with clinical CR, PR, NR. | Infliximab concentration will be measured in peripheral blood sample (serum). Response is defined as complete resolution of GVHD symptoms and normalization of the biochemical parameters of inflammation. | At day 56 after starting infliximab treatment | 
| Percentage of infection during follow-up | Viral reactivation (Cytomegalovirus and Epstein-Barr virus), bacterial and fungal infection will be evaluated by medical records | At 6 months after starting infliximab treatment | 
| Percentage of infection during follow-up | Viral reactivation (Cytomegalovirus and Epstein-Barr virus), bacterial and fungal infection will be evaluated by medical records | At 12 months after starting infliximab treatment | 
| Percentage of chronic GVHD | Evaluated by medical records | At 6 months after starting infliximab treatment | 
| Percentage of chronic GVHD | Evaluated by medical records | At 12 months after starting infliximab treatment | 
| Percentage of relapse | Evaluated by medical records | At 6 months after starting infliximab treatment | 
| Percentage of relapse | Evaluated by medical records | At 12 months after starting infliximab treatment | 
| Transplant-related mortality | Evaluated by medical records | At 6 months after starting infliximab treatment | 
| Overall survival | Evaluated by medical records | At 6 months after starting infliximab treatment | 
| Transplant-related mortality | Evaluated by medical records | At 12 months after starting infliximab treatment | 
| Overall survival | Evaluated by medical records | At 12 months after starting infliximab treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute graft-versus-host disease, Infliximab, TNFα, Hematopoietic Stem Cell Transplant