Complement and Graft-versus-host Disease
Condition: Allografted With Myeloablative Conditioning
MeSH terms: Graft vs Host Disease
Study type: Interventional

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.
    

Intervention name(s): Serum concentration /Serum inflammatory
Intervention type(s): Other
Intervention description(s): 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 model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Allogeneic haematopoietic stem cell transplantation (HSCT); Myeloablative conditioning for an haematological malignancy; Graft-versus-host disease (GvHD); Activation of complement system; Gut GVHD