A Retrospective Cohort Study: The Influence of MTHFR C677T and A1298C on the High-dose Methotrexate-Related Toxicities in Pediatric Patients With Non-Hodgkin Lymphoma

February 23, 2020 updated by: Xiao-Fei Sun, Sun Yat-sen University
We hypothesized that polymorphism MTHFR C677T and A1298C should be associated with HD-MTX-related toxicities in children with NHL. Therefore, we aimed to retrospectively explore their relationships in this analysis.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

INTRODUCTION: Non-Hodgkin lymphoma (NHL), the fourth most common malignancy across the pediatric age spectrum, is a heterogeneous group of lymphoid malignancies. In children, NHL comprises four main wide categories: lymphoblastic lymphoma (LBL), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large cell lymphoma (ALCL). The current overall survival rate of pediatric NHL exceeds 80% due to dramatic progress in developing risk-adapted curative therapy (1), in which methotrexate (MTX) plays a crucial part.

MTX is used to treat a variety of cancers. A high-dose MTX (HD-MTX) regimen, referred to the administration of a dosage ranging from 0.5g/m2 to 12.0g/m2 or even higher, is commonly used to treat childhood acute lymphoblastic leukemia (ALL), lymphoma and pediatric osteosarcoma. Despite its wide range of therapeutic efficacy, the toxicities of HD-MTX including reversible myelosuppression, nausea, vomiting, diarrhea, hepatotoxicity, nephrotoxicity, neurotoxicity, and particularly oral mucositis should not be neglected. Accumulating pharmacogenetic studies have revealed that polymorphisms of enzymes involved in folate pathway could lead to variability in response to MTX and HD-MTX-related toxicities in various malignancies. The most two extensively studied SNPs of MTHFR in relation to the toxicities of MTX are the C677T variant (Ala222Val, rs1801133) and A1298C variant (Glu 429Ala, rs1801131), both dampening the enzyme activity by 40-70%.

However, limited evidence is available in pediatric NHL, with results varying considerably in different studies. Therefore, the aim of this retrospective study was to evaluate the influence of C677T and A1298C polymorphisms on HD-MTX-related toxicities in children with NHL treated according to BFM-modified protocols.

PATIENTS & METHODS：We reviewed the medical records of all pediatric patients who were diagnosed as NHL and received HD-MTX-based chemotherapy at the dose of 5g/m2 in Sun Yat-sen University Cancer Center between March 2014 and March 2019. Data were analyzed by chi-square test.

Study Type

Observational

Enrollment (Actual)

93

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Guangdong
      • Guangzhou, Guangdong, China, 510060
        • Sun Yat-sen University Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 14 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

  1. Age：≤ 18 years old；
  2. Diseases: the four main types of NHL, including lymphoblastic lymphoma (LBL), Burkitt's lymphoma (BL), anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL)
  3. Treatment: HD-MTX-based chemotherapy at the dose of 5g/m2;
  4. Genotype: MTHFR C677T and A1298C；
  5. Center：Sun Yat-sen University Cancer Center，Guangzhou, P.R China;
  6. Time period: between March 2014 and March 2019.

Description

Inclusion Criteria: patients who were:

  • Aged ≤ 18 years old；
  • Diagnosed as the four main types of NHL, including lymphoblastic lymphoma (LBL), Burkitt's lymphoma (BL), anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL);
  • Treated with HD-MTX therapy at the dose of 5g/m2;
  • Genotyped by PCR following Sanger with respect to MTHFR C677T and A1298C
  • With complete medical records.

Exclusion Criteria: patients who were:

  • Aged >18 years old；
  • Diagnosed as cancer types other than the four main types of NHL;
  • Treated with no HD-MTX therapy or at the dose other than 5g/m2;
  • Not genotyped by PCR following Sanger with respect to MTHFR C677T and A1298C
  • With incomplete medical records .

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Retrospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Observations of HD-MTX-related toxicities
Time Frame: 3 weeks
We recorded the toxicities that occurred to the patients after the MTX infusion, including hematological suppression, hepatotoxicity, nephrotoxicity, oral mucositis, vomiting and diarrhea.
3 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sun Yat-sen University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2014

Primary Completion (Actual)

March 1, 2019

Study Completion (Actual)

March 1, 2019

Study Registration Dates

First Submitted

February 23, 2020

First Submitted That Met QC Criteria

February 23, 2020

First Posted (Actual)

February 25, 2020

Study Record Updates

Last Update Posted (Actual)

February 25, 2020

Last Update Submitted That Met QC Criteria

February 23, 2020

Last Verified

February 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SCCCG-NHL-2017

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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