Treatment of Chronic Graft Versus Host Disease With Arsenic Trioxide
Condition: Chronic Graft-Versus-Host Disease; Immune System Diseases
MeSH terms: Bronchiolitis Obliterans Syndrome; Graft vs Host Disease; Immune System Diseases
Intervention: Arsenic Trioxide Injectable Solution
Intervention description: Each patient will receive eleven perfusions of arsenic trioxide (0,15 mg/kg/Day - IV administration) over a 4 weeks period (one cycle).
Patients in partial response after the 1st cycle of ATO will be eligible to receive a second cycle of ATO as consolidation therapy. A delay of 8 weeks (from the first infusion of ATO) will be observed between the two cycles of ATO therapy.
The study duration will be 2 years (12 months recruitment + 12 months follow-up).
Intervention MeSH terms: Arsenic Trioxide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: cGvHD; Arsenic Trioxide; Hematology

Summary:

      This study aims to evaluate the early chronic GvHD events (first line therapy), if the
      addition of arsenic trioxide to standard therapy with corticosteroids, with or without
      cyclosporine, will be effective in controlling chronic GvHD and to reduce the duration of
      corticosteroid therapy
    

Eligibility criteria:

        Inclusion Criteria:

          -  Adult patients (≥18 years) who have received a first allogeneic stem cell
             transplantation for a hematological disease (any source of hematopoietic stem cells is
             authorized; any category of conditioning regimen prior to allo-SCT is authorized; any
             type of stem cell donors is authorized)

          -  Confirmed diagnosis of a first episode of chronic GvHD requiring systemic
             immunosuppressive therapy (any prior GvHD prophylaxis previously used is accepted).
             Chronic GvHD diagnosis is defined according to the NIH Working Group Consensus.
             Chronic GvHD diagnosis will be based on the evaluation of the severity of the
             different clinical manifestations including:

               -  Performance status evaluation

               -  Cutaneous evaluation measured by the percentage of extension or the presence of
                  sclerotic features. If relevant, confirmation with a biopsy should be performed
                  whenever possible

               -  Oral symptoms

               -  Ocular symptoms

               -  Gastro-intestinal symptoms

               -  Evaluation of liver involvement (total bilirubin, transaminases and alkaline
                  phosphatases)

               -  Pulmonary function evaluation

               -  Evaluation of the musculoskeletal manifestations, especially the amplitude of the
                  relevant articulations

               -  Genital tract symptoms

          -  Signed informed consent

          -  Absence of contra-indications to the use of ATO

          -  Subjects affiliated with an appropriate social security system

          -  Men must use a medically acceptable method of contraception throughout the treatment
             period and for at least 4 months and 10 days following the last treatment
             administration

          -  Women who are of childbearing potential must have a negative serum pregnancy test and
             agree to use a medically acceptable method of contraception throughout the study and
             for 3 months following the end of the study

          -  Patient not participating or not having participated in a clinical study in the 30
             days prior to his/her inclusion in the study

        Exclusion Criteria:

          -  Patient developing acute GvHD (whether early or "late onset" form)

          -  Patients developing overlap GvHD as defined by the 2014 NIH Working Group Consensus
             (presence of one or more acute GvHD manifestations in a patient with a diagnosis of
             chronic GvHD)

          -  A "mild" form of chronic GvHD not requiring systemic immunosuppressive therapy

          -  A "moderate" form of chronic GvHD limited to one organ site not requiring systemic
             immunosuppressive therapy

          -  Patient receiving mycophenolate mofetil

          -  Not the first episode of chronic GvHD needing systemic immunosuppressive therapy

          -  Second allogeneic stem cell transplant

          -  Severe cardiac diseases (congestive heart failure (NYHA class III), recent myocardial
             infarction (in the past 6 months before the inclusion), histories of unexplained
             syncope, ...)

          -  Significant arrhythmias, electrocardiogram (EKG) abnormalities:

          -  Congenital QT syndromes

          -  History or presence of significant ventricular or atrial tachyarrhythmia

          -  Clinically significant resting bradycardia (< 50 beats per minutes)

          -  QTc>450msecformenand>470msecfor women on screening EKG (using the QTcF formula)

          -  Right bundle branch block plus left anterior hemiblock, bifascicular block

          -  Central or peripheral neuropathy

          -  Neutrophils < 0.5 × 109/L

          -  Platelets < 50 × 109/L

          -  Potassium ≤ 4 mEq/l*

          -  Magnesium ≤ 1.8 mg/dl*

          -  Calcium ≤ 2.15 mmol/l*

          -  Hepatic impairment due to a suspected or proven liver damage, other than direct
             hepatic cGvHD involvement

          -  PT < 50%

          -  Renal impairment (creatinine ≥ 100 μmol/l)

          -  Uncontrolled systemic infection which in the opinion of the investigator is associated
             with an increased risk of the patients' death within 1 month after the start of
             therapy

          -  Severe neurological or psychiatric disorders

          -  Denied informed consent

          -  Pregnancy

          -  Women breastfeeding at selection and throughout the treatment period

               -  If abnormal at selection, to be corrected and re-validated following electrolytes
                  infusion, before inclusion and each drug perfusion.