Electronic Database for the Follow up of the ATG_FamilyStudy
Condition: GVHD, Chronic; Acute Leukemia; Stem Cell Transplant Complications
Study type: Observational [Patient Registry]

Summary: 
      Allogeneic hematopoietic stem cell transplantation (HSCT) is capable of definitive cure of
      acute leukemias. The most important post-transplant complication is graft vs host disease
      (GVHD) which can be substantially decreased by the addition of anti-T lymphocyte globulin
      (ATG-Grafalon) to the standard GVHD prophylaxis (cyclosporin and methotrexate) without any
      increase in relapses and infections (Kroger et al NEJM 2016, ClinicalTrials.gov number,
      NCT00678275). In the ATG_familystudy (prospective, randomised, multicenter study) a decrease
      in the incidence of chronic GVHD (from 67.8% to 32.2%) was observed after the addition of ATG
      (10 mg/kg for three days ,from day -3 to -1) to the standard GVHD prophylaxis in the setting
      of acute leukemias in any remission, receiving peripheral blood stem cells from an HLA
      identical sibling donor after myeloablative preparative regimen. In particular, the GVHD
      extensive form was reduced from 52.4% to 7.6%. The study has been closed in 2014 with a
      minimum follow up of 2 years from transplant. The investigators would like to evaluate the
      longer term follow up of this study.
    

Detailed description: 
      In the ATG_familystudy (prospective, randomised, multicenter study) a decrease in the
      incidence of chronic GVHD (from 67.8% to 32.2%) was observed after the addition of ATG (10
      mg/kg for three days from day -3 to -1) to the standard GVHD prophylaxis in the setting of
      acute leukemias in any remission, receiving peripheral blood stem cells from an HLA identical
      sibling donor after myeloablative preparative regimen. In particular, the GVHD extensive form
      was reduced from 52.4% to 7.6%. The study has been closed in 2014 with a minimum follow up of
      2 years from transplant.

      The primary endpoint is the creation of a multicenter electronic database with data of the
      patients previously enrolled in the ATG_family study, NCT00678275; the data collection will
      last ten years. Schedule of the follow-up will have be until death and will be stopped any
      time if patient will retire the consent.

      The database will allow to evaluate:

        -  Long term mortality of enrolled patients, with and without GVHD

        -  Long term relapse after allogeneic HSCT in acute leukemia patients

        -  Prognostic factors in the overall population and according to the randomization arm

        -  Recovery of working activity

      Study design

      Multicenter, observational, prospective cohorting study (electronic database) with a
      retrospective phase.

      Prospective phase:

      the electronic database will include patients enrolled in the ATG_familystudy and routinely
      followed up at the Hematological Institutions participating to the study.

      Retrospective phase:

      data collection will review all patients enrolled in the ATG familystudy (medical chart
      review) and already dead or lost at follow up after the end of the ATG_familystudy by medical
      chart review (Feb 2014).

      The electronic database will include all patients enrolled in the ATG_familystudy.

      Inclusion criteria:

        -  patients included in the ATG_familystudy (NCT00678275)

        -  informed consent given

      Exclusion criteria: none

      Treatment: no treatment is envisaged; patients are followed up according to standard clinical
      practice and international guidelines.

      Visit and evaluation

      Prospective phase: patients will be followed with visits (mainly as outpatients), laboratory
      and instrumental tests, phone contacts as provided for the clinic route.

      Retrospective phase: medical chart review

      Informed consent: patients will be asked to sign the written consent during a visit as an
      outpatient or inpatient, if required.

      Confidentiality of collected information:

      the principal investigator is the responsible of data treatment. Collected data will be
      analyzed by statistical methods in anonymous way in order to obtain the information
      representing the aim of the study. The electronic database will be accessible only by
      authorized persons. The principal investigator and the coworkers will have the access to
      data: everyone will be obliged to data confidentiality.

      Electronic database

        -  The electronic database will include all patients enrolled in the ATG_familystudy. The
           data collection about hospital admittance and medical evaluations performed as
           outpatient will be done by medical records/charts analysis. In this way, biographical
           data, anamnestic data and any information about signs and symptoms at the onset of
           disease, diagnostic roadmap and treatment will be collected.

        -  For patients unreachable by phone details given by the patients or for patients already
           dead, data will be taken by the analysis of the medical charts or by the Office of vital
           statistics, after EC approval. Patients lost at follow up are patients unreachable in
           anyway by the details given by the patient him/herself.

        -  In the electronic database data on patients enrolled in the ATGfamilystudy will be
           included from the date of EC approval. For dead and lost at follow up patients data will
           be recorded retrospectively.

      Statistical analysis

      The investigators will use cumulative incidence analysis to assess chronic GVHD-free survival
      and relapse-free survival and labeled death before the event of interest as a competing risk.
      Death from relapse will be used as a competing risk for the cumulative incidence analysis of
      death without relapse. Overall survival will be assessed with the use of Kaplan- Meier
      analysis. Further treatment- group comparisons were performed with the use of chi-square
      tests for nominal data, Mann-Whitney U-tests for ordinal data, and analyses of variance for
      interval or ratio-scale data. Exploratory, post hoc, Cox multiple regression analysis was
      used for subgroup analyses and for the purpose of determining the effect on the incidence of
      chronic GVHD and on overall survival of recipient age, first versus second remission, acute
      lymphoblastic versus acute myeloid leukemia, cytogenetic risk, risk of underlying disease,
      difference between the sex of the donor and the sex of the recipient, cytomegalovirus
      positivity in the recipient, type of conditioning, CD34+ cells transplanted, grade of acute
      GVHD and chronic GVHD (time dependent [i.e., the corresponding event can occur at different
      points in time after transplantation]) in addition to treatment assignment (ATG vs. non-ATG)
      in the original ATG_familystudy. Confidence intervals for the differences in risk according
      to treatment group will be determined with the use of Wilson's method. Cumulative incidence
      analyses will be performed with the use of NCSS statistical software, version 9, and R
      statistical software, version 2.10.1 (cmprsk package). IBM SPSS Statistics software, version
      22.0, will be used for all other analysis.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The electronic database will include all patients enrolled in the ATG_familystudy
        (NCT00678275).

        Multicenter, observational, prospective cohorting study (electronic database) with a
        retrospective phase.

        Prospective phase:

        the electronic database will include patients enrolled in the ATG_familystudy and routinely
        followed up at the Hematological Institutions participating to the study.

        Retrospective phase:

        data collection will review all patients enrolled in the ATG familystudy (medical chart
        review) and already dead or lost at follow up after the end of the ATG_familystudy by
        medical chart review (Feb 2014)
      
Keywords: anti-T lymphocytic globulin (ATG); allogeneic stem cell transplant; prophylaxis of GVHD