Clinical trial NCT05362630: Infliximab Efficacy, TDM and Serum TNFα Levels in Pediatric HSCT Recipients With aGVHD: Prospective Observational Study
Official title: 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Graft Versus Host Disease, Acute
Hematopoietic Stem Cell Transplantation
Keywords: Graft-Versus-Host Disease
Hemopoietic Stem Cell Transplant
Infliximab
Therapeutic Drug Monitoring
Clinical response
Population Pharmacokinetic Analysis
Lead sponsor: University of Pisa
Sponsor class: OTHER
First posted: 2022-05-05
Enrollment: 28
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children (0-18 years old) who undergo a HSCT and subsequently, develop an acute GVHD and receive infliximab

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Correlation between TNFalpha and infliximab plasma concentrations at day +56 of treatment
timeFrame: Day 56 after the start of infliximab administration
Secondary outcomes:
measure: Correlation between TNFalpha and infliximab plasma concentrations at day +7 of treatment
timeFrame: Day +7 after the start of infliximab administration
measure: Relationship between baseline TNFalpha plasma concentration and aGVHD overall severity
timeFrame: From day -7 up to day -1 from the start of infliximab administration
measure: Clinical response to infliximab
timeFrame: Day +56 of treatment
measure: Infliximab plasma concentrations according to clinical response
timeFrame: From day +7 up to day +56 of treatment
measure: Percentage of transplant-related deaths and infections during follow-up
timeFrame: From +6 months up to +1 year after treatment
measure: Retreatment rate with infliximab after the first dose
timeFrame: From +90 days from treatment begin up to +1 year
measure: Safety of drug treatment
timeFrame: From day +100 up to +1 year post-HSCT
measure: Overall survival (OS)
timeFrame: From day +100, up to +1 year after HSCT
Other outcomes:
Locations:
city: Trieste
country: Italy
facility: IRCCS Burlo Garofolo
Study officials:
affiliation: IRCCS Burlo Garofolo - Trieste, Italy
name: Natalia Maximova, MD
role: STUDY_DIRECTOR
References:
citation: Maximova N, Nistico D, Riccio G, Maestro A, Barbi E, Faganel Kotnik B, Marcuzzi A, Rimondi E, Di Paolo A. Advantage of First-Line Therapeutic Drug Monitoring-Driven Use of Infliximab for Treating Acute Intestinal and Liver GVHD in Children: A Prospective, Single-Center Study. Cancers (Basel). 2023 Jul 13;15(14):3605. doi: 10.3390/cancers15143605.