Genome-wide Single Nucleotide Polymorphism (SNP) Array-based Approach to Predict Chemoresponse and Survival in Patients With Acute Lymphoblastic Leukemia

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Brief Title

Genome-wide Single Nucleotide Polymorphism (SNP) Array-based Approach to Predict Chemoresponse and Survival in Patients With Acute Lymphoblastic Leukemia

Official Title

Genome-wide Single Nucleotide Polymorphism (SNP) Array-based Approach to Predict Chemoresponse and Survival in Patients With Acute Lymphoblastic Leukemia

Brief Summary

      Acute lymphoblastic leukemia (ALL) is not a single disease, but a composite of heterogeneous
      subgroup. Accordingly, more sophisticated classification in ALL is essential to achieve
      further improvement of treatment outcomes. However, only a few genetic markers are revealed
      to have significant prognostic implications in ALL patients. The current study is designed to
      stratify the ALL patients according to their prognosis and to predict their outcomes by a
      pharmacogenetic approach. A predictive model will be generated from 130 genotypes in adult
      ALL patients diagnosed at the Samsung Medical Center (SMC), Sungkyunkwan University School of
      Medicine, Seoul,Korea between 1994 and 2008. The validation of the predictive model will be
      performed using an independent external cohort of ALL patients.

        1. Definition of the cohort: two hundred ALL patients from the SMC as a test set, another
           100 patients from the SMC as a first validation set, and another 150 independent
           external patients as second external validation set. DNAs will be extracted and stored
           from patients' samples collected at the time of diagnosis.

        2. In the test set, genotypes will be determined using a MALDI-TOF based platform
           (Sequenom, San Diego, CA, USA) for 130 SNPs of the candidate genes involved in DNA
           repair pathway, drug metabolism/transport pathway and folate metabolism pathway.

        3. Bioinformatic analyses will be performed to identify around 13 genotypes (10%) having
           strongest predictive significance out of these 130 SNPs in terms of their treatment
           outcomes, drug toxicity and prognosis in the test set.

        4. These 13 genotypes will be validated in the first cohort of 100 ALL patients using a
           multivariate Cox's proportional hazard model.

        5. The predictive model will be built up based on Cox's proportional hazard model derived
           from 13 candidate genotypes and clinical risk factors.

        6. The predictive model based on pharmacogenetic information will be validated again in the
           second, independent external cohort of 150 ALL patients.

      Definite prognostic value was not established for genetic or molecular markers in acute
      lymphoblastic leukemia (ALL) except BCR/ABL fusion gene. The current study attempts to build
      up a predictive model based on single nucleotide polymorphisms (SNPs) with pharmacogenetic
      approach using 130 genotypes in the multiple candidate pathways such as DNA repair pathway,
      drug metabolism / transport pathway and folate metabolism pathway. The predictive model based
      on SNPs will be generated and validated with respect to treatment outcomes, drug toxicity and
      prognosis in adult ALL patients.

      The present study will demonstrate that: 1) Pharmacogenetic information derived from SNPs
      involved in the DNA repair pathway, drug metabolism/transport pathway and folate metabolism
      pathway, is helpful to predict the treatment outcomes, drug toxicity and prognosis in ALL
      patients; 2) Predictive model derived from pharmacogenetic information will be effective and
      reasonable approach to stratify ALL patients according to their clinical outcomes; 3) The
      SNP-based predictive model could be reasonably applied to the treatment of ALL patients, thus
      becoming a basis for further improvement of treatment outcome; 4) Finally, this project will
      enhance and facilitate the pharmacogenetic research in the hematology area, thus make the
      team to lead the pharmacogenetic research in the world.
    



Study Type

Observational


Primary Outcome

response rate

Secondary Outcome

 overall survival and progression-free survival

Condition

Acute Lymphoblastic Leukemia


Study Arms / Comparison Groups

 adult acute lymphoblastic leukemia
Description:  Patients were diagnosed as adult acute lymphoblastic leukemia.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

200

Start Date

February 2010



Eligibility Criteria

        Inclusion Criteria:

          -  patients with core binding factor positive acute myeloid leukemia

          -  18 years or older

          -  patients were treated with standard chemotherapy

          -  patients with available medical record and stored bone marrow specimen at time of
             diagnosis

        Exclusion Criteria:

          -  no definitive criteria
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Dong Hwan Kim, M.D.,Ph.D., +82-2-3410-1768, [email protected]

Location Countries

Korea, Republic of

Location Countries

Korea, Republic of

Administrative Informations


NCT ID

NCT01079507

Organization ID

2009-06-060



Study Sponsor

Samsung Medical Center


Study Sponsor

Dong Hwan Kim, M.D.,Ph.D., Principal Investigator, Division of Hematology and Oncology/Samsung Medical Center


Verification Date

March 2010