Clinical trial NCT01520623: Complement and Graft-versus-host Disease
Official title: Role of Complement System in Human Allogeneic Haematopoietic Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Allografted With Myeloablative Conditioning
Keywords: Allogeneic haematopoietic stem cell transplantation (HSCT)
Myeloablative conditioning for an haematological malignancy
Graft-versus-host disease (GvHD)
Activation of complement system
Gut GVHD
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Clinical haematology and BMT unit,Necker Hospital, Paris
name: Clinical haematology and BMT unit,Saint Antoine Hospital, Paris
name: Clinical haematology and BMT unit,Saint Louis Hospital,Paris
name: European Georges Pompidou Hospital
First posted: 2012-01-30
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Activation of the complement system and the development of acute gut GvHD
timeFrame: 12 weeks
Secondary outcomes:
measure: Overall survival
timeFrame: 2 years
measure: Overall survival without relapse
timeFrame: 2 Years
Other outcomes:
Locations:
city: Paris
country: France
facility: Saint Louis Hospital
city: Paris
country: France
facility: Saint Antoine Hospital
city: Paris
country: France
facility: Necker Hospital
Study officials:
affiliation: Saint Antoine Hospital
name: Marie-Thérèse RUBIO, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: