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Acute Graft Versus Host Disease

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Infliximab

Natalia Maximova, MD

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.

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.

Plasma samples to quantitate TNFalpha and infliximab concentrations

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

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

Correlation analysis between TNFalpha and infliximab plasma concentrations at day +56 of treatment

Correlation analysis between TNFalpha plasma concentrations at day +7 of treatment

Correlation analysis between TNFalpha plasma concentrations and the severity of aGVHD

Percentage of patients who achieve Complete Response (CR), Partial Response (PR), Non-Response (NR) to infliximab treatment for acute GVHD

Values of plasma concentrations of infliximab according to complete response, partial response and no-response (CR, PR, NR, respectively)

Percentage of transplant-related mortality (TRM), viral reactivation (EBV, CMV), bacterial and fungal infection during follow-up

Percentage of patients who require a new treatment with infliximab after at least 3 months after the first course

Percentage of patients who survive and free from bacterial and fungal infections after HSCT

University of Pisa

Associate Professor of Pharmacology

Neoplasms

Skin and Connective Tissue Diseases

Sarcoma

Sarcoma, Ewing

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Osteosarcoma

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

Ewing Sarcoma

Antineoplastic Agents

Melphalan

Thiotepa

All the patient who are affected by refractory or resistant or relapsed Soft tissue sarcoma o Ewing sarcoma who find an HLA compatible allogeneic donor and are submitted to Stem cell transplantation

administration of 15 mg/kg of thiotepa + 140 mg/sqm of melphalan followed by infusion of allogeneic hemopoietic stem cell

Allogeneic hemopoietic stem cell transplant

Arcangelo Prete, MD, PhD, PI

This is a perspective multicentric study for the treatment of patients aged equal or less than 60 years and submitted to an allogeneic hematopoietic stem cell transplantation from an HLA compatible related or unrelated donor because affected by resistent or refractory or relapsed after autologous stem cell transplantation Ewing Sarcoma or Soft tissues sarcoma who did not benefit from conventional therapy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Infliximab Efficacy, TDM and Serum TNFα Levels in Pediatric HSCT Recipients With aGVHD: Prospective Observational Study	NCT05362630	Graft Versus Ho... Hematopoietic S...		- 18 Years	University of Pisa
Infliximab Efficacy, TDM and Serum TNFα Levels in Pediatric HSCT Recipients With aGVHD: Prospective Observational Study	NCT05362630	Graft Versus Ho... Hematopoietic S...		- 18 Years	University of Pisa
Hematopoietic Stem Cell Transplantation From Human Leukocyte Antigen (HLA) Compatible Donor in Ewing Sarcomas and Soft Tissues Sarcomas	NCT00998361	Ewing Soft Tissue Sar...	Allogeneic hemo...	1 Month - 60 Years	IRCCS Azienda Ospedaliero-Universitaria di Bologna

Spots Global Cancer Trial Database for hemopoietic stem cell transplant