Complement and Graft-versus-host Disease

NCT ID: NCT01520623

Last Updated: 2015-04-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 70 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-30
• Study Completion Date: 2013-07-31

Brief Summary

Allogeneic haematopoietic stem cell transplantation (HSCT) often remains the only curative treatment for haematological malignancies. The anti-leukaemic effect of allogeneic HSCT, called the GvL (Graf-versus-Leukemia) effect, is often associated to the development of an immune response against healthy recipient cells leading to a graft-versus-host disease (GvHD) in 20 to 70% of allogeneic HSCT. Acute GvHD, that usually targets the skin, the gastrointestinal (GI) tract and the liver, is an important cause of morbidity and mortality after allogeneic HSCT, particularly in the case of GI GvHD. The main goal of the research in the field of allogeneic HSCT is to determine strategies that could decrease the risk of GvHD without affecting the GvL effect. According to GVHD experimental models, it is likely that GvL but not GvHD may occur in the absence of inflammatory signals induced by the transplant-associated conditioning. Based on this hypothesis, we have chosen to analyse the role of Complement system in patients who received allogeneic HSCT. Indeed, Complement system is a major actor of inflammation and in the generation of tissue destruction, both of which are involved in the physiopathology of GVHD. Furthermore, it might be a potential target of some available inhibitory drugs (purified C1-Inhibitor, anti-C5 antibodies) in a preventive or curative manner in such patients. Preliminary data obtained from 34 allografted patients in our institution suggest that Complement activation by the classical pathway is correlated to the occurrence of GI GVHD. The goal of our current project, in order to confirm these preliminary results in a larger series, is to explore Complement system activation in patients who received allogeneic HSCT in three Adult Hematology departments in Paris fot two years and to correlate the biological results to the clinical events occurring after HSCT.

Detailed Description

The study will be performed in allografted patients with myeloablative conditioning for an haematological malignancy from 3 adult transplant units.

Patients will be followed for at least12 months after transplantation and blood samples drawn before conditioning and once a week for 12 weeks after transplantation to analyze:

• serum concentration of Complement factors (C3, C4, B factor), Complement regulatory proteins (C1-inhibitor, I and H Factors) and analysis of the surface expression of Complement regulatory molecules such as CD46, CD55 and CD59.
• serum inflammatory cytokine levels

In addition, patients with clinical signs of gut GVHD will be explored by gastrointestinal endoscopy to perform gut biopsies. C5b9 deposure will be then analyzed by immunohistochemistry on GVHD lesions.

Activation of complement system will be defined by a decrease of complement factor levels of 50% and values under lower physiological limits. The clinical evolution and the inflammatory cytokine profile of patients with such an activation profile will be compared to that of those without complement activation.

A data base containing biological and clinical data will be established. Biological results will be correlated to post-transplant clinical events, in particular the occurrence of gut GVHD but also non relapse mortality and overall survival by adapted statistical tests (comparison of percentages by Chi-2 of Pearson, comparison of survival curves by logrank, multivariate analysis by logistic regression test or cox model).

The number of required patients will be established by comparison of the percentage of gut GVHD in the patients with or without complement activation. Based on our preliminary results, we hypothesize that 2/3 patients will not have complement activation among whose 20% will develop acute gut GVHD. We expect an increase of acute gut GVHD up to 60% of the patients with complement activation that would represent 1/3 of the cohort.

With a bilateral alpha risk of 5% and a power of 80%, the number of required patients is 23 in the activated group and 46 in the non activated group, thus a total of 69 patients.

Conditions

Allografted With Myeloablative Conditioning

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Allografted patients

Allografted patients with myeloablative conditioning for an haematological malignancy. Patients will be followed for at least 12 months after transplantation and blood samples drawn before conditioning and once a week for 12 weeks after transplantation to analyze the serum concentration of Complement factors (C3, C4, B factor), Complement regulatory proteins (C1-inhibitor, I and H Factors) and analysis of the surface expression of Complement regulatory molecules such as CD46, CD55 and CD59 and the serum inflammatory cytokine levels

Group Type: OTHER

Serum concentration /Serum inflammatory

Intervention Type: OTHER

Allografted patients with myeloablative conditioning for an haematological malignancy. Patients will be followed for at least 12 months after transplantation and blood samples drawn before conditioning and once a week for 12 weeks after transplantation to analyze the serum concentration of Complement factors (C3, C4, B factor), Complement regulatory proteins (C1-inhibitor, I and H Factors) and analysis of the surface expression of Complement regulatory molecules such as CD46, CD55 and CD59 and the serum inflammatory cytokine levels

Interventions

Serum concentration /Serum inflammatory

Allografted patients with myeloablative conditioning for an haematological malignancy. Patients will be followed for at least 12 months after transplantation and blood samples drawn before conditioning and once a week for 12 weeks after transplantation to analyze the serum concentration of Complement factors (C3, C4, B factor), Complement regulatory proteins (C1-inhibitor, I and H Factors) and analysis of the surface expression of Complement regulatory molecules such as CD46, CD55 and CD59 and the serum inflammatory cytokine levels

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Allografted patients with myeloablative conditioning for an haematological malignancy
• Age > 18 years old and < 65 years.
• The patient must have access to social insurance according to local regulations.
• Patient must give a written informed consent (personally signed and dated) before completing any study related procedure

Exclusion Criteria

• Age < 18 years old and > 65 years
• Patient with active infection HIV, HTLV1, Hepatite B ou C
• Uncontrolled infection(s), (i.e. documented bacterial, parasitical, or fungal infection).
• Patient with lupus
• Patient with transaminases > 5N, TP<30% with Facteur V < 30% before allogreffe
• Creatinine clearance < 50ml/min
• Absence of any psychological condition potentially hampering signing informed consent
• Patient refused to sign informed consent

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Clinical haematology and BMT unit,Necker Hospital, Paris

UNKNOWN

Sponsor Role: collaborator

Clinical haematology and BMT unit,Saint Antoine Hospital, Paris

UNKNOWN

Sponsor Role: collaborator

Clinical haematology and BMT unit,Saint Louis Hospital,Paris

UNKNOWN

Sponsor Role: collaborator

European Georges Pompidou Hospital

OTHER

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marie-Thérèse RUBIO, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Saint Antoine Hospital

Locations

Saint Louis Hospital

Paris, , France

Saint Antoine Hospital

Paris, , France

Necker Hospital

Paris, , France

Countries

France

References

Notarantonio AB, D'aveni-Piney M, Pagliuca S, Ashraf Y, Galimard JE, Xhaard A, Marcais A, Suarez F, Brissot E, Feugier P, Urien S, Bouazza N, Jacquelin S, Meatchi T, Bruneval P, Fremeaux-Bacchi V, Peffault De Latour R, Hermine O, Durey-Dragon MA, Rubio MT. Systemic complement activation influences outcomes after allogeneic hematopoietic cell transplantation: A prospective French multicenter trial. Am J Hematol. 2023 Oct;98(10):1559-1570. doi: 10.1002/ajh.27030. Epub 2023 Jul 22.

Reference Type: DERIVED

PMID: 37483161 (View on PubMed)

Other Identifiers

CRC 08025

Identifier Type: -

Identifier Source: org_study_id