Clinical Relevance of DNMT and HDAC Gene SNP on the Response to Decitabine Therapy for Myelodysplastic Syndrome

Sponsor

Samsung Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT04515914

Collaborator

(none)

Enrollment

Location

Duration (Months)

4.9

Patients Per Site Per Month

Study Details

Study Description

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:

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome

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.

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.

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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

68 participants

Observational Model:

Case-Control

Time Perspective:

Retrospective

Official Title:

Clinical Relevance of DNA Methyltransferase and Histone Deacetylase Gene Single Nucleotide Polymorphism in Myelodysplastic Syndrome

Study Start Date :

Sep 1, 2009

Actual Primary Completion Date :

Oct 1, 2010

Actual Study Completion Date :

Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Decitabine therapy The patients are treated with decitabine at least 1 cycles
non-Decitabine therapy The Patients are diagnosed as MDS and do not be treated with decitabine therapy

Outcome Measures

Primary Outcome Measures

Overall response rate [18 months]

Secondary Outcome Measures

Time to progression or hematologic improvement [18 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:
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.

Historical control group

Male and female aged 18 years or older.
The patients diagnosed with (primary or secondary) MDS

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.