A Phase II Pilot Study to Assess the Presence of Molecular Factors Predictive for Hematologic Response in Myelodysplastic Syndrome Patients Receiving Deferasirox Therapy.
Condition: Myelodysplastic Syndrome
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome
Intervention: Bone marrow aspirate; Deferasirox
Intervention description: Patients experiencing a hematological response and patients not experiencing a hematological response while on deferasirox treatment received a new bone marrow aspirate in order to investigate the presence of differential gene expression between those two groups; Patients are already on commercial deferasirox before entering the study.
Intervention MeSH terms: Deferasirox
Phase: Phase 2
Study type: Interventional
Primary purpose: Basic Science
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: deferasirox; MDS; RNA expression; predictive biomarker

Summary:

      Several previous studies (clinical and non-clinical) hypothesize that treatment with
      deferasirox causes a hematological improvement in transfused patients with low and
      intermediate-1 risk myelodysplastic syndrome. The purpose of this study was to assess the
      presence of genetic biomarkers predictive for hematologic response by the use of gene
      expression profiling of bone marrow aspirates obtained from MDS patients with or without
      hematological response.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent obtained prior to any other study procedure,

          -  Males or females ≥ 18 years of age,

          -  MDS according to WHO criteria lasting ≥ 14 weeks at the time of screening, IPSS score
             <1.5 (low and intermediate-1 risk patients) at the time of screening using the IPSS
             score of 1997

          -  Treatment with deferasirox:

          -  Only for the responder group: Treatment with deferasirox for prevention or treatment
             of IOL for at least 14 weeks before screening.

          -  Only for the non-responder group: Treatment with deferasirox for at least 9 months for
             prevention or treatment of IOL before screening to exclude patients with a late
             hematological response.

          -  Only for responder-group: Patient with hematological response defined according to the
             IWG criteria of 2006 which must last at least 8 weeks, confirmed by the scientific
             advisory committee. In case a hematological response is identified retrospectively,
             the confirmation will be based on the last available blood result showing
             hematological response according to the IWG criteria of 2006. In this case, an
             archived bone marrow sample at the moment of response has to be available in order to
             be eligible. This archived bone marrow had to be taken at the moment when
             hematological response was present for at least 8 weeks and was still ongoing at the
             moment of sampling, according to the IWG criteria of 2006 in order to be eligible.
             When a bone marrow sample was taken after the hematological response had already
             disappeared, the sample is not eligible for further analysis.

          -  Only for non-responder group: confirmation by the scientific advisory committee that
             patient is eligible based on matched-pairing and confirmation of no hematological
             response. Minimal requirements for matched pairing include age, sex, IPSS score,
             hemoglobin level, transfusion need at baseline, treatment duration with deferasirox
             and time since MDS diagnosis. Pairing can be extended according to level of
             leukopenia, thrombocytopenia, serum ferritin level at baseline, comorbidities and
             transfusion history. More details about pairing are described in the protocol. In case
             a non-responder is identified retrospectively and an archival bone marrow is available
             at that documented time of non-response, this can be used for further analysis. In
             that case, an interval of 4 weeks between blood sampling for documentation of
             non-response and bone marrow sampling is allowed.

          -  Bone marrow aspirate/RNA taken at the time of MDS diagnosis (at baseline) retrievable
             from patient's hospital. This should be checked by the treating
             hematologist/oncologist before referring the patient for potential inclusion to the
             study. This aspirate/RNA has to be preserved under the right circumstances in order to
             ensure the quality of the RNA. The sample most be frozen viably, meaning controlled
             rate freezing and addition of a protector dimethyl sulfoxide DMSO and preserved in
             -80°C. Preservation of cells that are lysed in a lysis buffer upon arrival in the lab,
             and stored at -20°C until RNA-extraction are also useful for this study.

        Exclusion Criteria:

          -  Known concomitant presence of anemia due to iron, B12 or folate deficiencies,
             auto-immune or hereditary hemolysis, gastro-intestinal bleeding or medication induced
             anemia at the time of screening,

          -  Known infection with viral hepatitis B (HBV) or viral hepatitis C (HCV) defined as the
             presence in blood of HBV antigens in absence of HB antibodies, or presence of HCV
             antibodies at the time of screening,

          -  Known history of positivity to human immunodeficiency virus (HIV) measured by
             enzyme-linked immunosorbent assay (ELISA) or western blot at the time of screening,

          -  Patient participating in another clinical trial or receiving any investigational drug
             at the time of screening within 1 month prior to study inclusion

          -  History of other malignancy within the last five years, with the exception of basal
             skin carcinoma or cervical carcinoma in situ or completely resected colonic polyps
             carcinoma in situ

          -  Concomitant treatment with other drugs known or suspected to elicit hematological
             response. (azacitidine, hematopoietic growth factors, granulocyte colony stimulating
             factors, valproate, lenalidomide, thalidomide, ATG, cyclosporine, arsenic
             trioxide).When patients are still receiving red blood cell transfusions, patients are
             still eligible for study inclusion as long as they meet the IWG criteria of 2006

          -  Female patients who are pregnant or breast feeding