Infliximab Efficacy, TDM and Serum TNFα Levels in Pediatric HSCT Recipients With aGVHD: Prospective Observational Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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 (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. Therefore, the study is aimed at evaluating the role of TNFalpha concentration in acute GVHD, the fluctuation of its plasma levels, and the 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 HSCT Recipients With Acute Graft-versus-host Disease: a Prospective Observational Study

Conditions
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Graft Versus Host Disease, Acute, Hematopoietic Stem Cell Transplantation

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: Follow up < 6 months. Active fungal or bacterial infection with life-threatening clinical condition (shock or respiratory distress that needs 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 TNFalpha and infliximab plasma concentrations at day +56 of treatment | Correlation analysis between TNFalpha and infliximab plasma concentrations at day +56 of treatment | Day 56 after the start of infliximab administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between TNFalpha and infliximab plasma concentrations at day +7 of treatment | Correlation analysis between TNFalpha plasma concentrations at day +7 of treatment | Day +7 after the start of infliximab administration | 
| Relationship between baseline TNFalpha plasma concentration and aGVHD overall severity | Correlation analysis between TNFalpha plasma concentrations and the severity of aGVHD | From day -7 up to day -1 from the start of infliximab administration | 
| Clinical response to infliximab | Percentage of patients who achieve Complete Response (CR), Partial Response (PR), Non-Response (NR) to infliximab treatment for acute GVHD | Day +56 of treatment | 
| Infliximab plasma concentrations according to clinical response | Values of plasma concentrations of infliximab according to complete response, partial response and no-response (CR, PR, NR, respectively) | From day +7 up to day +56 of treatment | 
| Percentage of transplant-related deaths and infections during follow-up | Percentage of transplant-related mortality (TRM), viral reactivation (EBV, CMV), bacterial and fungal infection during follow-up | From +6 months up to +1 year after treatment | 
| Retreatment rate with infliximab after the first dose | Percentage of patients who require a new treatment with infliximab after at least 3 months after the first course | From +90 days from treatment begin up to +1 year | 
| Safety of drug treatment | Percentage of patients who survive and free from bacterial and fungal infections after HSCT | From day +100 up to +1 year post-HSCT | 
| Overall survival (OS) | OS after HSCT | From day +100, up to +1 year after HSCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft-Versus-Host Disease, Hemopoietic Stem Cell Transplant, Infliximab, Therapeutic Drug Monitoring, Clinical response, Population Pharmacokinetic Analysis