Clinical trial NCT04515914: Clinical Relevance of DNMT and HDAC Gene SNP on the Response to Decitabine Therapy for Myelodysplastic Syndrome
Official title: Clinical Relevance of DNA Methyltransferase and Histone Deacetylase Gene Single Nucleotide Polymorphism in Myelodysplastic Syndrome
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Myelodysplastic Syndrome
Keywords: DNA methyltransferase gene
Histone deacetylase gene
Single nucleotide polymorphism
Decitabine
Myelodysplastic syndrome
Lead sponsor: Samsung Medical Center
Sponsor class: OTHER
First posted: 2020-08-17
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This study will include the patients who signed the subject informed consent form among the patients with MDS who were chosen to be treated with decitabine, plus additional MDS patients as a historical control.

Brief summary: Recent investigations have demonstrated that DNMT gene polymorphisms can contribute to the inter-individual variants in DNMT expression. Accordingly, we hypothesized that the DNMT and HDAC genes SNPs could predict the outcomes of decitabine therapy for myelodysplastic syndrome. Prospective collection of DNA from peripheral blood will be performed in the patients with MDS before commencement of decitabine therapy. We will evaluate the efficacy decitabine therapy according to the DNMT or HDAC gene SNPs in terms of following parameters: 1) hematolotic response (HR) or improvement (HI), or requirement of decitabine dose to achieve HR or HI, 2) complete (CR) or partial response (PR), or requirement of decitabine dose to achieve CR or PR, and 3) time to relapse or progression of MDS.

The objective of this study is 1) to determine genotypes from DNA samples from MDS patients receiving Decitabine therapy, 2) to determine the association of clinical outcomes (HR, HI, CR, PR or time to progression to leukemia) following decitabine therapy with DNMT or HDAC genotypes, and 3) to analyze the impact of cytogenetic risk on the response or leukemic evolution following decitabine therapy for MDS.

Detailed description: This study will include the patients who signed the subject informed consent form among the patients with MDS who were chosen to be treated with Decitabine (Part I), plus additional 140 MDS patients as a historical control (Part II). Approximately, 68 patients will be included who satisfy the following inclusion and exclusion criteria in the Part I study.

Prospective collection of DNA from peripheral blood will be performed in the patients with MDS before commencement of decitabine therapy. We will evaluate the efficacy decitabine therapy according to the DNMT or HDAC gene SNPs in terms of following parameters: 1) hematolotic response (HR) or improvement (HI), or requirement of decitabine dose to achieve HR or HI, 2) complete (CR) or partial response (PR), or requirement of decitabine dose to achieve CR or PR, and 3) time to relapse or progression of MDS.

Genotyping will be undertaken using the Sequenom® iPLEX platform™, according to the manufacturer's instructions (www.sequenom.com; Sequenom Inc, San Diego, CA, USA). Whole blood samples will be obtained according to the declaration of Helsinki. DNA will be extracted using the Puregene DNA purification Kit (Gentra Systems Inc, Minneapolis, MN, USA). The detection of SNPs will be performed by the analysis of primer extension products generated from previously amplified genomic DNA using a Sequenom chip-based matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry platform. Multiplex SNP assays will be designed using SpectroDesigner software (Sequenom). Ninety-six well plates containing 2.5 ng DNA in each well will be amplified by PCR following the specifications of Sequenom. Unincorporated nucleotides in the PCR product will be deactivated using shrimp alkaline phosphatase. Allele discrimination reactions will be conducted by adding the extension primer(s), DNA polymerase, and a cocktail mixture of deoxynucleotide triphosphates and di-deoxynucleotide triphosphates to each well. MassExtend clean resin (Sequenom) will be added to the mixture to remove extraneous salts that could interfere with MALDI-TOF analysis. The primer extension products will be then cleaned and spotted onto a SpectroChip. Genotypes will be determined by spotting an aliquot of each sample onto a 384 SpectroChip (Sequenom), which is subsequently read by the MALDI-TOF mass spectrometer.

All statistical tests will be two-sided with the significance level set as 0.05 unless otherwise stated. The statistical data will be obtained using an SAS version 9.1 (SAS Institute, Cary NC, USA). Followings are the endpoints for the study.

1. Primary endpoint evaluation data

   • Response rate: A response rate will be obtained and its confidence interval estimated to be evaluated through chi-square test. If the main endpoints which may influence the final evaluation must be controlled, stratified analysis (Cochran-Mantel-Haenzel, etc.) will be conducted. If all the subjects' characteristic endpoints must be controlled, the logistic regression model will be used for analysis.
2. Secondary endpoint evaluation data

   * Overall survival: survival will be evaluated from the registration day to death through Kaplan-Meier method.
   * Progression free survival: : The time of progression from MDS to AML and death from any cause. Progression free survival will be analyzed through Kaplan-Meier method.

Eligibility criteria: 1. Inclusion Criteria:

   1. Decitabine treatment group

      * Male and female aged 18 years or older.
      * The patients diagnosed with (primary or secondary) MDS
      * Patients with an IPSS score of ≥ Int-1
      * Patients treated with Decitabine at least 1 cycles.
      * Signed and dated informed consent before the start of genetic study using genomic DNA derived from blood sample.
   2. Historical control group

      * Male and female aged 18 years or older.
      * The patients diagnosed with (primary or secondary) MDS
2. Exclusion Criteria:

   * Patients diagnosed with acute myelogenous leukemia (AML, bone marrow stem cell counts exceeding 20%) or other progressive malignant diseases.
   * Diagnosis of chronic myelomonocytic leukemia (CMML) or MDS/MPD excluded.

Primary outcomes:
measure: Overall response rate
timeFrame: 18 months
Secondary outcomes:
measure: Time to progression or hematologic improvement
timeFrame: 18 months
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
Study officials:
affiliation: Division of Hematology and Oncology/Samsung Medical Center
name: Dong Hwan Kim, M.D.,Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: